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1
Cheung, Man-sze, and 張敏思. "Characterization of Leukemic stem cells in acute myeloid Leukemia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40687582.
Повний текст джерела
2
Cheung, Man-sze. "Characterization of Leukemic stem cells in acute myeloid Leukemia." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B40687582.
Повний текст джерела
3
Yaseen, Mumtaz. "Proteomics of Acute Myeloid Leukemia:." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-69882.
Повний текст джерела
4
Gunnarsson, Niklas. "Chronic myeloid leukemia and cancer." Doctoral thesis, Umeå universitet, Medicin, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-141144.
Повний текст джерелаАнотація:
Background Chronic myeloid leukemia (CML) is a relatively rare hematological malignancy with a constant incidence of approximately 90 new cases each year in Sweden (0.9 cases/100 000 inhabitants). The etiology is largely unknown but high doses of ionizing radiation are a known but rare risk factor. The treatment options were for a long time limited to chemotherapies i.e. hydroxyurea and busulfan, interferon’s and allogeneic hematopoietic stem cell transplantation and the median survival were only about four years. Since the beginning of the 21st century a new way of treating CML has been introduced, the tyrosine kinase inhibitors (TKI), leading to a rapid decrease in leukemic cells and symptoms. Due to the TKIs, the overall 5-year survival is nowadays approximately 85 % and CML patients have time to develop other diseases, including other malignancies. The aims of this thesis was to investigate the present and future prevalence of CML and the prevalence of other malignancies prior and subsequent to the diagnosis of CML, malignancies among first-degree relatives of persons with CML. In addition, the incidence of autoimmune and chronic inflammatory diseases among patients with CML was also investigated. Methods From the Swedish CML register, data over nearly all Swedish CML patients from 2002 and forward were obtained for paper II-IV. For paper I, the Swedish cancer register was used to identify all Swedish CML patients since 1970 and the Swedish cause of death register was used to identify an eventual date of death for these patients. With a constant incidence and the relative survival rates for CML patients between 2006 and 2012 as a model, the present and future prevalence was calculated. For paper II-IV, data from the Swedish cancer register was used to identify other malignancies than CML. For paper II, information about autoimmune and chronic inflammatory diseases was retrieved from the Swedish national patient register. For paper II and IV, five controls matched for year of birth, gender and county of residence were randomly selected from the Swedish register of the total population. To calculate odds ratio (OR), conditional logistic regression was used. To calculate the risk of a second malignancy for paper III, Standardized incidence ratio (SIR) was used. In paper IV, first-degree relatives (parents, siblings and offsprings) for both cases and controls were retrieved from the Swedish multi-Generation Register, where persons born later than 1932 and registered in Sweden at some time since 1961 are registered. Results Prevalence and survival As shown in paper I, the 5-year overall survival for CML patients increased remarkably from 0.18 to 0.82 between 1970 and 2012. The prevalence increased from 3.9 to 11.9 per 100 000 inhabitants in Sweden between 1985 and 2012. By assuming no further improvements in relative survival as compared to the survival rates between 2006 and 2012, the prevalence by 2060 is expected to increase to 22.0 per 100 000 inhabitants. This corresponds to 2 587 CML patients as compared to 1 137 CML patients in 2012. Malignancies, autoimmune and chronic inflammatory diseases prior to CML In study II, more than 45 000 person-years of follow-up were evaluated in 984 CML patients diagnosed between 2002 and 2012. With an OR of 1.47 (95 % CI 1.20–1.82) and 1.55 (95 % CI 1.21–1.98), respectively, the prevalence of prior malignancies and autoimmune diseases were significantly increased as compared to matched controls. On the other hand, no association between CML and chronic inflammatory diseases was shown. Second malignancies In 868 CML patients, diagnosed between 2002 and 2011, 52 malignancies were observed in the Swedish cancer register, as shown in paper III. When compared to expected rates in the background population, a significantly increased risk of second malignancies with a SIR of 1.52 (95 % CI 1.13–1.99) was shown. When looking at specific cancer types, gastrointestinal as well as nose and throat cancer were significantly increased. Familial aggregation of malignancies 984 CML patients were identified in paper IV. However, 184 had a birth date prior to 1932, subsequently only 800 patients were analyzed. Among them, 4 287 first-degree relatives were identified, compared to 20 930 first-degree relatives of the matched controls. 611 malignancies were retrieved; no significant increase of malignancies in first-degree relatives of CML patients was shown (OR 1.06; 95 % CI: 0.96–1.16). Conclusion Since CML patients nowadays have a high survival rate, the calculations in this thesis shows that the prevalence of CML will almost double by 2060. CML patients have an increased risk of developing malignancies prior and subsequent to the diagnosis of CML, suggesting a hereditary or acquired predisposition to develop cancer. Since there is no familial aggregation of malignancies in CML patients, a hereditary predisposition to develop cancer is unlikely to be part of the pathogenesis of CML, leaving an acquired predisposition more likely.
5
VARINELLI, MARCO. "MODELLING CHRONIC MYELOID LEUKEMIA IN ZEBRAFISH." Doctoral thesis, Università degli studi di Brescia, 2021. http://hdl.handle.net/11379/544088.
Повний текст джерела
6
Cornforth, Terri Victoria. "Characterising the cell biology of leukemic stem cells in acute myeloid leukemia." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:654b2176-fd50-427e-86f2-74e928054bef.
Повний текст джерелаАнотація:
Acute Myeloid leukemia (AML) is an aggressive haematological malignancy that mainly affects the elderly. Relapse is common and is thought to be due to the presence of chemotherapy resistant leukemic stem cells (LSC). Within the CD34+ disease (>5% of the blast cells expressing CD34) , two subtypes have been identified; an LMPP/GMPlike expanded type and a MPP/CMP-like expanded type, the former is the most common, accounting for around 80% of CD34+ AML. Both the GMP-like and LMPPlike expanded populations show LSC activity. To improve our understanding of the disease and gain better insight in to how to develop treatments, the molecular basis of the disease needs to be investigated. I investigated miRNAs in the GMP/LMPP-like expanded AML. miRNAs are small non-coding RNAs involved in the regulation of mRNA. In recent years miRNAs have been shown to be implicated in many different diseases. To investigate the role miRNAs play in AML, miRNA expression was profiled in leukemic and normal bone marrow. Bioinformatic analysis was then used to examine the different miRNA expression profiles between normal and leukemic marrow. Our study showed that miRNAs are dysregulated in AML. miRNAs from the miR-17-92 and its paralogous cluster miR-106b-92 were amongst the miRNAs to be found down regulated in AML As had been seen previously at an mRNA level, on an miRNA level the LSC populations more closely resembled more mature progenitor populations than HSC and MPP populations, however the LSC populations did display an aberrant stem cell-like miRNA signature.
7
Zhang, Lu [Verfasser]. "Immunogenicity of leukemia stem cells in acute myeloid leukemia / Lu Zhang." Ulm : Universität Ulm. Medizinische Fakultät, 2012. http://d-nb.info/1020022574/34.
Повний текст джерела
8
García, Montolío Marc 1991. "The Role of PHF19 in myeloid leukemia." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/667911.
Повний текст джерелаАнотація:
Polycomb group (PcG) of proteins are a group of highly conserved epigenetic regulators involved in many biological functions such as embryonic development, stem cell self-renewal, cell proliferation, and cancer. PHD finger protein 19 (PHF19) is an associated factor of Polycomb Repressor Complex 2 (PRC2) that has been proposed to regulated its activity in embryonic stem cells. PHF19 has been shown to be up-regulated in different human cancers as well as cancer cell lines. In particular, myeloid leukemia cell lines show increased levels of PHF19, yet little is known about its function. Here, we have characterized the role of PHF19 in myeloid leukemia cell lines. We have demonstrated that PHF19 depletion decreases cell proliferation and induces erythroid differentiation. Mechanistically, we have demonstrated that PHF19 regulates the proliferation of chronic myeloid leukemia cell lines through its interaction with cell cycle regulator p21. Furthermore, we have observed that MTF2, a PHF19 homolog, occupies PHF19 target genes when PHF19 is depleted. Taken together, our results show that PHF19 is a key transcriptional regulator in myeloid leukemic cell lines and suggest that PHF19 inhibition could be a potential target to be explored for myeloid leukemia treatment.El complejo de proteínas Polycomb (PcG), es un grupo de reguladores epigenéticos altamente conservados que participan en distintas funciones biológicas como el desarrollo embrionario, la auto renovación de las células madre, la proliferación y están involucradas también en cáncer. La proteína PHD finger 19 (PHF19), es un factor asociado al complejo represor Polycomb 2 (PRC2). PHF19 ha sido propuesta como reguladora de la actividad de PRC2 en células madre embrionarias. También se ha visto que esta sobreexpressada en diferentes canceres y líneas celulares cancerígenas. Nosotros hemos demostrado que la eliminación de PHF19 disminuye la proliferación de las líneas celulares mieloides cancerígenas. Hemos demostrado que la depleción de PHF19 en las células de leucemia crónica mieloide las induce a diferenciarse hacia eritrocitos. Mecánicamente, hemos demostrado que PHF19 regula la proliferación de esta línea celular mediante su interacción con el regulador de ciclo celular p21. Además, hemos observado que MTF2, un homólogo de PHF19, se deposita en aquellos genes donde previamente estaba PHF19. En conjunto, nuestros resultados muestran que PHF19 es un factor transcripcional clave en líneas celulares mieloides y sugieren que la inhibición de PHF19 podría ser una potencial diana para ser explorada para el tratamiento de la leucemia mieloide.
9
Palle, Josefine. "Optimizing Chemotherapy in Childhood Acute Myeloid Leukemia." Doctoral thesis, Uppsala University, Department of Women's and Children's Health, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9189.
Повний текст джерелаАнотація:
Despite major advances in our understanding of the biology of childhood acute myeloid leukemia (AML) and the development of new cytotoxic drugs, the prognosis of long-term survival is still only 60-65 %.
In the present research, we studied the pharmacokinetics of drugs used in the induction therapy of childhood AML and performed in vitro drug sensitivity testing of leukemic cells from children with AML.
The aims of the studies were to correlate the results of the analysis to biological and clinical parameters and to identify subgroups of AML with specific drug sensitivity profiles in order to better understand why treatment fails in some patients and how therapy may be improved.
Blood samples were analysed to study the pharmacokinetics of doxorubicin (n=41), etoposide (n=45) and 6-thioguanine (n=50). Doxorubicin plasma concentration and total body clearance were correlated to the effect of induction therapy, and doxorubicin plasma concentration was an independent factor for complete remission, both in univariate and multivariate analysis including sex, age, and white blood cell count at diagnosis. For etoposide and 6-thioguanine no correlation was found between pharmacokinetics and clinical effect. Children with Down syndrome (DS) tended to reach higher blood concentrations of etoposide and thioguanine nucleotides, indicating that dose reduction may be reasonable to reach the same drug exposure as in children without DS.
Leukemic cells from 201 children with newly diagnosed AML, 15 of whom had DS, were successfully analysed for in vitro drug sensitivity by the fluorometric microculture cytotoxicity assay (FMCA). We found that samples from children with DS were highly sensitive to most drugs used in AML treatment. In non-DS children, the t(9;11) samples were significantly more sensitive to cytarabine (p=0.03) and doxorubicin (p=0.035) than other samples. The findings might explain the very favorable outcome reported in children with DS and t(9;11)-positive AML. A specific drug resistance profile was found for several other genetic subgroups as well. A detailed study of MLL-rearranged leukemia showed that cellular drug sensitivity is correlated both to partner genes and cell lineage, findings that support the strategy of contemporary protocols to include high-dose cytarabine in the treatment of patients with MLL-rearrangement, both in AML and acute lymphoblastic leukemia (ALL).
Our results indicate that drug resistance and pharmacokinetic studies may yield important information regarding drug response in different sub-groups of childhood AML, helping us to optimize future chemotherapy in childhood AML.
10
Watson, Alexander Scarth. "Autophagy in hematopoiesis and acute myeloid leukemia." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:2e66c5c3-4774-44d1-8345-d0dc827da16d.
Повний текст джерелаАнотація:
Acute myeloid leukemia (AML) develops following oncogenic alterations to hematopoietic stem (HSC) and progenitor cells (HSPCs) in the bone marrow, resulting in dysregulated proliferation of immature myeloid progenitors that interferes with normal hematopoiesis. Understanding the mechanisms of HSPC protection against damage and excessive division, and how these pathways are altered during leukemic progression, is vital for establishing effective therapies. Here, we show that autophagy, a lysosomal degradation pathway, is increased in HSPCs using a novel imaging flow cytometry autophagy assay. Loss of hematopoietic autophagy following deletion of key gene Atg5 resulted in increased HSC proliferation, leading to HSC exhaustion and bone marrow failure. Although erythrocyte and lymphocyte populations were negatively impacted by autophagy loss, myeloid cells showing immature characteristics were expanded. Deletion of Atg5 in an AML model resulted in increased proliferation under metabolic stress, dependent on the glycolytic pathway, and aberrant upstream mTOR signaling. Moreover, modulation of Atg5 altered leukemic response to culture with stromal cells. Finally, primary AML cells displayed multiple markers of decreased autophagy. These data suggest a role for autophagy in preserving HSC function, partially through suppression of HSPC proliferation, and indicate that decreased autophagy may benefit AML cells. We postulate that modulation of autophagy could help maintain stem cell function, for example during transplantation, and aid AML therapy in a setting-specific manner.
11
Abubakar, Aminu Abdussalam. "Chemotherapeutic responses of marine myeloid leukemias." Thesis, University of St Andrews, 1990. http://hdl.handle.net/10023/13522.
Повний текст джерелаАнотація:
The murine myeloid leukaemias employed in this study were induced in male CBA/H mice following irradiation with sublethal doses of X-ray. The responses of these leukaemic cell lines and normal (murine) bone marrow cells to cytosine arabinoside and mitoxantrone treatment in vitro were monitored. Both clonogenic, and nonclonogenic chemotherapeutic assays such as radioactive precursor uptake, dye-exclusion assay and autoradiography were employed to determine drug-induced cell lethality. In addition, the in vitro proliferative responses of the leukaemic cell lines and normal bone marrow cells to growth factors were determined using a [3H]thymidine uptake assay. Both cytarabine and mitoxantrone were as toxic to normal bone marrow cells as to leukaemic cells from most of the cell lines. Mitoxantrone appears to be more potent than cytarabine against leukaemic cells in vitro. However, it was also more toxic to normal bone marrow cells. Generally, combinations of cytarabine and mitoxantrone resulted in an additive cytotoxic effect. Mitoxantrone appears to have a narrow therapeutic margin when administered to leukaemia bearing mice in vivo. The response of the (SA7) myeloid leukaemic cell line to mitoxantrone was distinctly different from those reported for murine lymphoid leukaemias (P388 and L1210). Doubling the mitoxantrone dose within the therapeutic range was not accompanied by an increase in the number of long-term survivors (cures). Bone marrow cells of cured mice or normal(CBA/H) mice administered low doses of mitoxantrone became less sensitive to subsequent treatment with mitoxantrone in vitro . Doses of mitoxantrone that resulted in loss of protective effect by bone marrow cells of normal mice were toxic to leukaemia bearing mice. Primary and low cell dose transplant myeloid leukaemias were less responsive to growth factors as compared to the high cell dose passages. The SA2 leukaemic cell line grew in vitro without requirement for growth factors. However, no growth was observed in serum-free medium which suggests that serum was providing the stimulus for in vitro proliferation. Leukaemic bone marrow cells from the SA7 high cell dose passage cell line, were normally responsive to growth factors in vitro. However, at relapse following in vivo treatment with mitoxantrone, the leukaemic cells became significantly (P=0.04) growth factor insensitive. Bone marrow cells of normal mice retained growth factor sensitivity following in vivo treatment with mitoxantrone. Furthermore, bone marrow cells of mice cured of leukaemia by mitoxantrone treatment in vivo were responsive to growth factors. Recovery of growth factor responsiveness occurred when the recurrent leukaemic cells were passaged in normal mice. However, no recovery of growth factor sensitivity was observed when recurrent leukaemic cells were passaged in mice that received a single dose of mitoxantrone (0.75mg/Kg) two days previously. Even after passage in normal mice, the recurrent leukaemic cells were in some cases, significantly (P=0.012) resistant to mitoxantrone treatment in vitro. The degree of resistance appears to depend on the dose of mitoxantrone employed in the treatment of the leukaemia. However, passaging the recurrent leukaemia in mitoxantrone pretreated mice did not increase the level of resistance developed by the leukaemic cells. These results suggest that these myeloid leukaemic cell lines may be useful models for preclinical evaluation of chemotherapeutic agents.
12
Derolf, Åsa Rangert. "Predictors of prognosis in acute myeloid leukemia a clinical and epidemiological study /." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-788-7/.
Повний текст джерела
13
Xue, Liting. "Oncogene Function in Pre-Leukemia Stage of INV(16) Acute Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/740.
Повний текст джерелаАнотація:
The CBFbeta-SMMHC fusion protein is expressed in acute myeloid leukemia (AML) samples with the chromosome inversion inv(16)(p13;q22). This fusion protein binds the transcription factor RUNX with higher affinity than its physiological partner CBFbeta and disrupts the core binding factor (CBF) activity in hematopoietic stem and progenitor cells. Studies in the Castilla laboratory have shown that CBFbeta-SMMHC expression blocks differentiation of hematopoietic progenitors, creating a pre-leukemic progenitor that progresses to AML in cooperation with other mutations. However, the combined function of cumulative cooperating mutations in the pre-leukemic progenitor cells that enhance their expansion to induce leukemia is not known. The standard treatment for inv(16) AML is based on the use of non-selective cytotoxic chemotherapy, resulting in a good initial response, but with limited long-term survival. Therefore, there is a need for developing targeted therapies with improved efficacy in leukemic cells and minimal toxicity for normal cells.
Here, we used conditional Nras+/LSL-G12D; Cbfb+/56M; Mx1Cre knock-in mice to show that allelic expression of oncogenic N-RasG12D expanded the multi-potential progenitor (MPP) compartment by 8 fold. Allelic expression of Cbfbeta-SMMHC increased the MPPs and short-term hematopoietic stem cells (ST-HSCs) by 2 to 4 fold both alone and in combination with N-RasG12D expression. In addition, allelic expression of oncogenic N-RasG12D and Cbfbeta-SMMHC increases survival of pre-leukemic stem and progenitor cells. Differential analysis of bone marrow cells determined that Cbfb+/MYH11 and Nras+/G12D; vii Cbfb+/MYH11 cells included increased number of blasts, myeloblasts and promyelocytes and a reduction in immature granulocytes, suggesting that expression of N-RasG12D cannot bypass Cbfbeta-SMMHC driven differentiation block.
N-RasG12D and Cbfbeta-SMMHC synergized in leukemia, in which Nras+/G12D; Cbfb+/MYH11 mice have a shorter median latency than Cbfb+/MYH11 mice. In addition, the synergy in leukemogenesis was cell autonomous. Notably, leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC showed higher (over 100 fold) leukemia-initiating cell activity in vivo than leukemic cells expressing Cbfbeta-SMMHC (L-IC activity of 1/4,000 and 1/528,334, respectively).
Short term culture and biochemical assays revealed that pre-leukemic and leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC have reduced levels of pro-apoptotic protein Bim compared to control. The Nras+/G12D; CbfbMYH11 pre-leukemic and leukemic cells were sensitive to pharmacologic inhibition of MEK/ERK signaling pathway with increasing apoptosis and Bim protein levels but not sensitive to PI3K inhibitors. In addition, knock-down of Bcl2l11 (Bim) expression in Cbfbeta-SMMHC pre-leukemic progenitors decreased their apoptosis levels.
In collaboration with Dr. John Bushweller’s and other research laboratories, we recently developed a CBFbeta-SMMHC inhibitor named AI-10-49, which specifically binds to CBFbeta-SMMHC, prevents its binding to RUNX proteins and restores CBF function. Biochemical analysis in human leukemic cells showed that AI-10-49 has significant specificity in reducing the viability of leukemic cells expressing CBFbeta-SMMHC (IC50= 0.83μM), and negligible toxicity in normal cells. Likewise, mouse Nras+/G12D; viii Cbfb+/MYH11 leukemic cells were sensitive to AI-10-49 (IC50= 0.93μM). By using the NrasLSL-G12D; Cbfb56M mouse model, we also show that AI-10-49 significantly prolongs the survival of mice bearing the leukemic cells. Preliminary mechanistic analysis of AI-10-49 activity has shown that AI-10-49 increased BCL2L11 transcript levels in a dose and time dependent manner in murine and human leukemic cells, suggesting that the viability through BIM-mediated apoptosis may be targeted by both oncogenic signals.
My thesis study demonstrates that Cbfbeta-SMMHC and N-RasG12D promote the survival of pre-leukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define NrasLSL-G12D; Cbfb56M mice as a valuable genetic model for the study of inv(16) AML targeted therapies. For instance, the novel CBFbeta-SMMHC inhibitor AI-10-49 shows a significant efficacy in this mouse model. This small molecule will serve as a promising first generation drug for targeted therapy of inv(16) leukemia and also a very useful tool to understand mechanisms of leukemogenesis driving by CBFbeta-SMMHC.
14
Xue, Liting. "Oncogene Function in Pre-Leukemia Stage of INV(16) Acute Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2010. http://escholarship.umassmed.edu/gsbs_diss/740.
Повний текст джерелаАнотація:
The CBFbeta-SMMHC fusion protein is expressed in acute myeloid leukemia (AML) samples with the chromosome inversion inv(16)(p13;q22). This fusion protein binds the transcription factor RUNX with higher affinity than its physiological partner CBFbeta and disrupts the core binding factor (CBF) activity in hematopoietic stem and progenitor cells. Studies in the Castilla laboratory have shown that CBFbeta-SMMHC expression blocks differentiation of hematopoietic progenitors, creating a pre-leukemic progenitor that progresses to AML in cooperation with other mutations. However, the combined function of cumulative cooperating mutations in the pre-leukemic progenitor cells that enhance their expansion to induce leukemia is not known. The standard treatment for inv(16) AML is based on the use of non-selective cytotoxic chemotherapy, resulting in a good initial response, but with limited long-term survival. Therefore, there is a need for developing targeted therapies with improved efficacy in leukemic cells and minimal toxicity for normal cells.
Here, we used conditional Nras+/LSL-G12D; Cbfb+/56M; Mx1Cre knock-in mice to show that allelic expression of oncogenic N-RasG12D expanded the multi-potential progenitor (MPP) compartment by 8 fold. Allelic expression of Cbfbeta-SMMHC increased the MPPs and short-term hematopoietic stem cells (ST-HSCs) by 2 to 4 fold both alone and in combination with N-RasG12D expression. In addition, allelic expression of oncogenic N-RasG12D and Cbfbeta-SMMHC increases survival of pre-leukemic stem and progenitor cells. Differential analysis of bone marrow cells determined that Cbfb+/MYH11 and Nras+/G12D; vii Cbfb+/MYH11 cells included increased number of blasts, myeloblasts and promyelocytes and a reduction in immature granulocytes, suggesting that expression of N-RasG12D cannot bypass Cbfbeta-SMMHC driven differentiation block.
N-RasG12D and Cbfbeta-SMMHC synergized in leukemia, in which Nras+/G12D; Cbfb+/MYH11 mice have a shorter median latency than Cbfb+/MYH11 mice. In addition, the synergy in leukemogenesis was cell autonomous. Notably, leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC showed higher (over 100 fold) leukemia-initiating cell activity in vivo than leukemic cells expressing Cbfbeta-SMMHC (L-IC activity of 1/4,000 and 1/528,334, respectively).
Short term culture and biochemical assays revealed that pre-leukemic and leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC have reduced levels of pro-apoptotic protein Bim compared to control. The Nras+/G12D; CbfbMYH11 pre-leukemic and leukemic cells were sensitive to pharmacologic inhibition of MEK/ERK signaling pathway with increasing apoptosis and Bim protein levels but not sensitive to PI3K inhibitors. In addition, knock-down of Bcl2l11 (Bim) expression in Cbfbeta-SMMHC pre-leukemic progenitors decreased their apoptosis levels.
In collaboration with Dr. John Bushweller’s and other research laboratories, we recently developed a CBFbeta-SMMHC inhibitor named AI-10-49, which specifically binds to CBFbeta-SMMHC, prevents its binding to RUNX proteins and restores CBF function. Biochemical analysis in human leukemic cells showed that AI-10-49 has significant specificity in reducing the viability of leukemic cells expressing CBFbeta-SMMHC (IC50= 0.83μM), and negligible toxicity in normal cells. Likewise, mouse Nras+/G12D; viii Cbfb+/MYH11 leukemic cells were sensitive to AI-10-49 (IC50= 0.93μM). By using the NrasLSL-G12D; Cbfb56M mouse model, we also show that AI-10-49 significantly prolongs the survival of mice bearing the leukemic cells. Preliminary mechanistic analysis of AI-10-49 activity has shown that AI-10-49 increased BCL2L11 transcript levels in a dose and time dependent manner in murine and human leukemic cells, suggesting that the viability through BIM-mediated apoptosis may be targeted by both oncogenic signals.
My thesis study demonstrates that Cbfbeta-SMMHC and N-RasG12D promote the survival of pre-leukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define NrasLSL-G12D; Cbfb56M mice as a valuable genetic model for the study of inv(16) AML targeted therapies. For instance, the novel CBFbeta-SMMHC inhibitor AI-10-49 shows a significant efficacy in this mouse model. This small molecule will serve as a promising first generation drug for targeted therapy of inv(16) leukemia and also a very useful tool to understand mechanisms of leukemogenesis driving by CBFbeta-SMMHC.
15
Demajo, Meseguer Santiago 1985. "ZRF1-mediated transcriptional regulation in acute myeloid leukemia." Doctoral thesis, Universitat Pompeu Fabra, 2014. http://hdl.handle.net/10803/283478.
Повний текст джерелаАнотація:
Acute myeloid leukemia (AML) is frequently linked to epigenetic abnormalities and
deregulation of gene transcription, which lead to aberrant cell proliferation and accumulation of
undifferentiated precursors. ZRF1, a recently characterized epigenetic factor involved in
transcriptional regulation, is highly overexpressed in human AML, but it is not known whether
it plays a role in leukemia progression. In this thesis, we have investigated the function of
ZRF1-mediated transcriptional regulation in AML. We demonstrate that ZRF1 depletion
decreases cell proliferation, increases apoptosis and induces cell differentiation in human AML
cells. Treatment with retinoic acid (RA), a differentiating agent currently used to treat certain
AMLs, leads to a functional switch of ZRF1 from a negative regulator to an activator of
differentiation. At the molecular level, ZRF1 controls the RA-regulated gene network through
its interaction with the RA receptor α (RARα) and its binding to RA target genes. Our genomewide
expression study reveals that ZRF1 regulates the transcription of nearly half of RA target
genes. Consistent with our in vitro observations that ZRF1 regulates proliferation, apoptosis,
and differentiation, ZRF1 depletion strongly inhibits leukemia progression in xenograft mouse
models. Finally, ZRF1 knockdown cooperate with RA treatment in leukemia suppression in
vivo. Taken together, our results show that ZRF1 is a key transcriptional regulator in leukemia
progression and suggest that ZRF1 inhibition could be a novel strategy to be explored for AML
treatment.La leucèmia mieloide aguda (LMA) està relacionada freqüentment amb anomalies epigenètiques i desregulació de la transcripció gènica, que provoquen una proliferació cel·lular aberrant i l'acumulació de precursors indiferenciats. ZRF1, un factor epigenètic caracteritzat recentment i implicat en la regulació transcripcional, es troba altament sobreexpressat en la LMA humana, però es desconeix si juga cap paper en la progressió de la malaltia. En aquesta tesi, s'ha investigat la funció de ZRF1 en la regulació transcripcional en la LMA. Es demostra que el silenciament de ZRF1 provoca una disminució de la proliferació, un increment de l'apoptosi i una inducció de la diferenciació en cèl·lules de LMA humana. El tractament amb àcid retinoic (AR), un inductor de la diferenciació que es fa servir actualment per a tractar determinades LMAs, produeix un canvi funcional en ZRF1, que passa de repressor a activador de la diferenciació. A nivell molecular, ZRF1 controla la xarxa de gens regulada per l’AR a través de la seva interacció amb el receptor de l'AR α (RARα) i la seva unió als gens diana de l'AR. El nostre estudi d'expressió a nivell de tot el genoma revela que ZRF1 regula la transcripció de gairebé la meitat dels gens diana de l'AR. En concordança amb les nostres observacions in vitro que mostren que ZRF1 regula la proliferació, l'apoptosi i la diferenciació, el silenciament de ZRF1 provoca una forta inhibició en la progressió de la leucèmia en models de xenotrasplantament en ratolí. Finalment, el silenciament de ZRF1 coopera amb el tractament amb AR en la supressió de la leucèmia in vivo. Conjuntament, aquests resultats mostren que ZRF1 és un regulador transcripcional clau en la progressió de la leucèmia i suggereixen que la inhibició de ZRF1 podria ser una nova estratègia a explorar en al tractament de la LMA.
16
Belt, Alex J. "Zebrafish Model of MLL-Rearranged Acute Myeloid Leukemia." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5600.
Повний текст джерелаАнотація:
Acute myeloid leukemia (AML) is the second most common type of leukemia and accounts for 80% of adult acute leukemia cases and is characterized by the accumulation of poorly or undifferentiated myeloid blast cells. Standard treatment includes chemotherapy, which if unsuccessful, is followed by more rigorous chemotherapy as well as stem cell transplantation. Considering most patients are over the age of 45, these more rigorous therapies are not always possible, and as such, new therapies must be developed. Furthermore, AML patients harboring a chromosomal rearrangement involving Multiple Lineage Leukemia (MLL) that results in the expression of an MLL fusion protein exhibit far worse prognoses than patients without. In recent years, Danio rerio (zebrafish) has emerged as a powerful model organism for investigating human blood malignancies due to the conservation of hematopoiesis between humans and zebrafish. The first objective of this study was to develop a transient transgenic AML model in zebrafish, and the second objective was to determine if co-treatment with two medications currently in human trials for AML, Venetoclax and Flavopiridol, would be more effective than using either drug individually. In order to develop a transient transgenic AML model, we first developed a DNA construct encoding a known mixed lineage leukemia (MLL) fusion protein associated with human AML, MLL-ENL, driven by the zebrafish lysozyme C (lyz) promoter, which drives myeloid specific expression in zebrafish. We then microinjected single-cell zebrafish embryos with DNA encoding lyz driven MLL-ENL along with transposase mRNA to facilitate the genomic integration of MLL-ENL. Injected embryos were first tested for MLL-ENL expression, and subsequently tested for AML phenotypic characteristics, via whole mount in-situ hybridization (WISH) at 72 hours post fertilization (hpf). First, WISH analysis utilizing a human MLL riboprobe verified MLL-ENL expression in injected embryos, and WISH analysis utilizing the same MLL riboprobe revealed an expansion and clustering of MLL positive cells in injected embryos, characteristic of an AML phenotype. Embryos injected with MLL-ENL DNA were then treated with either DMSO (vehicle), 200 nanomolar (nM) Venetoclax, 200 nM Flavopiridol, or 200 nM Venetoclax and 200 nM Flavopiridol from 24 hpf to 72 hpf. MLL WISH analysis of injected and treated embryos revealed a reduction in MLL positive cells in both Venetoclax treated embryos and Flavopiridol treated embryos, and an even greater reduction in MLL positive cells in embryos treated with both Venetoclax and Flavopiridol, compared to controls. Although further analysis is required to be confident, these data suggest that we successfully developed an AML transient transgenic model in zebrafish. Furthermore, these data suggest that Venetoclax and Flavopiridol co-treatment could yield better outcomes for AML patients than treatment with either drug individually.
17
Bodini, M. "Genomics of treatment response in Acute Myeloid Leukemia." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/469570.
Повний текст джерелаАнотація:
Acute Myeloid Leukaemia (AML) is a cancer of the myeloid lineage of blood cells characterised by rapid growth of undifferentiated myeloid precursors that accumulate in the bone marrow and suppress normal haematopoiesis. It is the most common adult leukaemia with an estimated number of more than 60’000 new cases for the US in 2016. Despite the high rates of complete remissions achieved after treatment (60-80% in young adults), the number of patient that will result cured after induction and consolidation therapy is very low (~12%). The molecular basis of relapsing disease is still unclear and the small number of identified predictive factors has small predictive power. To date, chemotherapy induction treatment is similar for all patients and consists in the administration of mainly three drugs (fludarabine, cytarabine, and idarubicin). Prediction markers for the outcome of chemotherapy would instead reduce useless treatments and direct research through new possible therapeutic targets that would enhance AML treatment. In three successive studies, Ding et al., Corces-Zimmerman et al. and Krönke et al., described four possible behaviours for relapse patients: the return of the first leukaemia (dominant clone or a subclone), with or without additional evolution, or the emergence of ancestral clones, also in this case, with or without additional mutations. In this thesis, endowed of the NGS technologies advancement, we decided to delineate the possible process of relapse formation in order to be able in the future to predict which patients are more susceptible to relapse. Our experimental plan includes the whole exome analysis of 30 pairs of primary/relapsed AML samples using NGS to identify relapse-specific mutations, the bioinformatics analysis of the clonal evolution of the disease and the identification of pathways that correlate with the relapsing disease.
The methods for the analysis of NGS data, at present, are still in a refinement phase, especially for the high level analysis (detection of variants and definition of their role in the pathogenesis). We broadly analysed the existing methods for the treatment of NGS data (aligners, mutation callers, CNV callers and methods to reconstruct clonal composition) in order to determine those better fitting to our cohort of patients and purposes: occasionally, we had the possibility to choose the best tool meeting our investigative needs, discovering that other methods were valuable as well, in other cases we verified that more improvements are needed to obtain reliable results.
Our analysis shows that the genomic landscapes of primary and relapse AMLs are similar and in the majority of the patients (76%) some relapse clones were already present in the primary tumour and reappeared after chemotherapy at similar or augmented cellular frequencies. We also identified some functional gene categories (DNA methylation pathway, cohesin complex and chromatin modifiers) more prone to resistance and peculiar genes (e.g. ASXL1, TET2) presenting growing VAFs at relapse. In 4 out of 29 patients (14%) we were able to identify driver mutations in the blood sample of the complete remission at low frequency; we hypothesise that more sophisticated diagnostic tools, based on NGS analysis, would help in driving the treatment to obtain better outcomes for patients.
18
VALLETTA, SIMONA. "Recurrent SETBP1 mutations in atypical chronic myeloid leukemia." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2014. http://hdl.handle.net/10281/50227.
Повний текст джерелаАнотація:
Atypical chronic myeloid leukemia (aCML) is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes. aCML shares clinical and laboratory features with Chronic Myeloid Leukemia (CML), but it lacks the Philadelphia chromosome and the resulting BCR-ABL fusion gene. This crucial difference with CML points to a different pathogenetic process. Because no specific recurrent genomic or karyotypic abnormalities have been identified in aCML, and the molecular pathogenesis of this disease has remained elusive with a dismal outcome, we performed exome-sequencing of eight aCML patients, in order to identify new possible recurrent mutations. The presence of an identical mutation not previously involved in cancer in two different aCML cases altering SETBP1 gene, prompted us to resequence this particular gene in samples from additional subjects with aCML or other hematological malignancies and in cell lines representative of the most common human solid cancers. SETBP1 mutations were identified only in aCML and in the closely related disorders and represents the first gene shown to be enriched and recurrently mutated in aCML. Most SETBP1 mutations were located between codons 858 and 871 causing abrogation of a degron binding site for E3-ubiquitin β-TrCP1 and protection from proteasomal degradation. This causes accumulation of SETBP1 and SET protein, decreased PP2A phosphatase activity and higher proliferation rates. Individuals with SETBP1 mutations had higher white blood cell counts and worse prognosis, indicating SETBP1 as a possible valuable diagnostic tool in the differential diagnosis of MDS/MPN syndromes and their prognosis.
This study increases the knowledge of the mechanisms by which malignancy arises and will have important consequences for the diagnosis, prognosis and treatment of aCML and diseases associated with SETBP1 alterations.
19
Namasu, Carolina Yaeko [Verfasser]. "The role of ABR in myeloid differentiation and acute myeloid leukemia / Carolina Yaeko Namasu." Halle, 2017. http://d-nb.info/116614061X/34.
Повний текст джерела
20
Shipman, Robert Charles. "The molecular characterization of a common human myelogenous leukemia-associated antigen (CAMAL)." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/27530.
Повний текст джерелаАнотація:
Previous studies had demonstrated the presence of the p70 (CAMAL) molecule in human myeloid leukemia cells and the promyelocytic leukemia cell line HL60, but not in equivalent preparations of normal cells (Malcolm et al., 1982, 1984; Shipman et al., 1983; Logan et al., 1984). Subsequent studies demonstrated that the p70 (CAMAL) protein was detectable and expressed in human myeloid leukemia cells and the leukemic cell lines HL60, KG1, K562 and U937. The association of p70 (CAMAL) expression with human myeloid leukemia cells prompted its consideration as a candidate leukemia-associated antigen.
The demonstration, following CAMAL purification and peptide sequencing, that two tryptic peptides (tp27, tp31) displayed significant homology to sequences present in human serum albumin (HSA) and human alpha-1-fetoprotein (AFP), while one tryptic peptide (tp20) displayed unique peptide sequence, suggested that CAMAL might represent a protein that was structurally and functionally related to the albumins. Consequently, a comparative biochemical analysis of CAMAL and HSA was initiated.
The results of the comparative studies demonstrated that although CAMAL and HSA shared conformational antigenic determinants, both proteins were also shown to be distinct molecules by a number of other criteria. The possibility that the CAMAL preparation, used for protein sequencing and comparative studies, was contaminated with HSA was thought likely, in view of the HSA/AFP-related peptide sequences from the CAMAL tryptic peptide sequence analysis. However, other results, particularly the antibody reactivity and ligand binding studies, showed that the CAMAL preparation was not contaminated with HSA. The unique CAMAL tryptic peptide (tp20) sequence supported further the contention that CAMAL was a distinct protein with regions homologous to HSA and AFP.
Further analysis of the CAMAL molecule, through extensive protein sequencing, will be, in all likelihood, the only means by which to establish the degree of relatedness between CAMAL, HSA and AFP.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
21
Logan, Patricia Marie. "Detection and possible significance of a common leukemia-associated antigen, CAMAL, in human myeloid leukemia." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/28860.
Повний текст джерелаАнотація:
Human acute nonlymphoblastic or myelogenous leukemia (ANLL or AML) is a malignant disease of the bone marrow involving hemopoietic (blood-forming) cells of the myeloid lineage. ANLL is a complex neoplastic disease, whose fundamental nature is only partially understood despite intensive research. The disease is complicated by its apparent heterogeneity in terms of the degree of differentiation of hemopoietic stem cell involvement in different patients and the cellular expression of immunologically defined surface markers. The presence of a common antigen in myelogenous leukemia (CAMAL) has been previously identified. This thesis examines the expression of the CAMAL marker in or on bone marrow (BM) and peripheral blood (PB) cells using a monoclonal antibody-based indirect immunoperoxidase slide test. Increased numbers of CAMAL-positive cells were found in or on BM and PB of myeloid leukemia patients (with acute or chronic forms of the disease) compared with those found in normals or most lymphoid malignancies. Results presented herein have demonstrated that fluctuations in CAMAL BM values (% positive cells) correlated with survival time prior to relapse. In a blind study, ANLL patients Whose CAMAL BM values decreased post-chemotherapy had significantly (p < 0.025) longer first remission times (x = 19.2 months) than patients with increasing or static CAMAL BM values (x = 6.8 months). CAMAL BM values were often observed to increase during remission, prior to relapse, suggesting the presence of residual subclinical disease. Addition of excess purified leukemia-derived CAMAL to an in vitro myeloid progenitor cell assay caused profound inhibition of normal CFU-c growth but had no inhibitory effect on CFU-c growth from myeloid leukemia patients in active disease states. Depletion of CAHAL from normal plasma and conditioned media (sources of numerous hemopoietic growth regulatory factors) caused significant inhibition of normal, but not myeloid leukemic, CFU-c growth. These results indicated that myeloid leukemic cells possessed apparent differences in responsiveness to CAMAL-mediated hemopoietic regulation compared to normal cells. Lack of responsiveness to inhibition by leukemia-derived CAMAL may facilitate dominance of the malignant clone over normal cells.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
22
Slape, Christopher Ian. "Molecular characterisation of translocations involving chromosome band 1p36 in acute myeloid leukaemia." Title page, table of contents and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09phs6313.pdf.
Повний текст джерелаАнотація:
"October 2002" Bibliography: leaves 159-198. This thesis describes the mapping of the breakpoints of three different chromosome rearrangements, all involving 1p36, in acute myeloid leukaemia (AML) patients, and an investigation into the molecular outcomes of these rearrangements.
23
Doepfner, Kathrin T. "Targeting receptor tyrosine kinase signaling in acute myeloid leukemia /." Zürich, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253043.
Повний текст джерела
24
Prenkert, Malin. "On mechanisms of drug resistance in acute myeloid leukemia." Doctoral thesis, Örebro universitet, Hälsoakademin, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-10603.
Повний текст джерелаАнотація:
In this thesis focus has been to increase the knowledge and understanding of some of the mechanisms responsible for drug resistance in acute myeloid leukemia, as well as identify possibilities to predict drug resistance at diagnosis. We have studied the intracellular behavior of cytostatic drugs and their main metabolites (paper I) and the cellular response to cytostatic drugs (paper III). A new flow cytometry in vitro chemosensitivity assay was developed, to enable identification of viable myeloid cells and determination of drug sensitivity (paper II). Finally, possible new markers involved in drug resistance were investigated (paper IV). In conclusion we found that idarubicin and daunorubicin are equally toxic at the same intracellular concentrations. The contribution of the main metabolites to the cytotoxic effects of idarubicin and daunorubicin, in both drug sensitive and drug resistant human myeloid leukemia cells, is low. It is most likely the pharmacokinetic properties of idarubicin and daunorubicin that confer their main cytotoxic effect. With the new flow cytometry chemosensitivity assay we selectively identified viable CD13/CD33 expressing myeloid cells and found that the cytotoxicity results correlated to clinical parameters, such as secondary AML and resistant disease. Short-term exposure of leukemia cell lines with different levels of drug resistance to ara-C revealed that Pgp mRNA and protein ex-pression levels, as well as GSTπ mRNA levels, were rapidly up-regulated. Clinically, this up-regulation may be of importance for the sequential scheduling of daunorubicin and ara-C during the induction treatment of AML. CRIM1 has never been studied in the context of drug resistance before. We show for the first time that baseline expression of CRIM1 mRNA is much higher in drug resistant leukemia cells compared to drug sensitive cells. We also found a co-variance between CRIM1 and Pgp mRNA expression levels in leukemia cell lines with different levels of drug resistance, suggesting that CRIM1 may be useful as a marker of drug resistance.
25
Rothe, Katharina. "Characterization of novel therapeutic targets in chronic myeloid leukemia." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/56175.
Повний текст джерелаАнотація:
The identification of BCR-ABL1 as the key molecular event in chronic myeloid leukemia (CML) has revolutionized treatment opportunities for early phase patients. Imatinib mesylate (IM) and other ABL1 tyrosine kinase inhibitors (TKIs) have been introduced into the clinic with remarkable effects. However, initial and acquired resistance, relapse and in particular, the persistence of CML stem cells upon TKI therapy represent critical challenges and warrant the identification of predictive biomarkers and novel, distinct targets for improved treatment strategies.
In this work, I investigated how CML stem and progenitor cells survive TKI therapy through intrinsic and bone marrow (BM) niche-associated mechanisms. I revealed that the core autophagy protease ATG4B, and the focal adhesion protein and serine/threonine kinase Integrin-linked kinase (ILK) play crucial roles in CML, and that they can be successfully targeted with small molecule inhibitors.
By comparing the expression of various core autophagy genes and proteins, ATG4B was identified as potential biomarker in CML to predict IM-responders versus IM-nonresponders prior to the initiation of therapy. Furthermore, my studies illustrated that deregulation of ATG4B is critical to autophagy, survival and growth of CML stem and progenitor cells. Inhibition or suppression of ATG4B decreased CML cell viability significantly and sensitized leukemic cells to TKI treatment highlighting ATG4B as a novel target in CML.
ILK was identified as a differentially expressed gene between CD34⁺ CML patient cells and healthy donors by RNA-sequencing (RNA-seq) analysis, and the importance of the ILK protein and its kinase functions in mediating TKI responses and resistance in CML stem and progenitor cells was demonstrated by ILK inhibitor (QLT0267) and ILK suppression studies. Moreover, various in vitro and in vivo assays showed that the simultaneous kinase inhibition of ILK and BCR-ABL1 is effective in targeting both leukemic stem and progenitor cells, including quiescent CML cells, and in the presence of stromal cells of the BM microenvironment that make TKI monotherapies ineffective.
Overall, these studies provide the first evidence of the importance of ATG4B and ILK in CML, and their potential as novel therapeutic targets for improved combination treatments with TKIs to specifically eliminate CML stem and progenitor cells.Medicine, Faculty of
Medical Genetics, Department of
Graduate
26
Holt, Bronno van der. "Translational studies in elderly patients with acute myeloid leukemia." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2007. http://hdl.handle.net/1765/10514.
Повний текст джерела
27
Vo, Thanh-Trang. "Mitochondrial Priming Determines Chemotherapeutic Response in Acute Myeloid Leukemia." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10384.
Повний текст джерелаАнотація:
Gain- and loss-of-function studies of the BCL-2 family of proteins have shown that they can impact chemotherapeutic sensitivity. However, cells contain myriad anti-apoptotic and pro-apoptotic BCL-2 family members making it difficult to predict cell fate decisions based on the initial conditions of these proteins. BH3 profiling is a tool that measures mitochondrial priming, the readiness of a cell to die through the intrinsic (or mitochondrial) apoptotic pathway. Priming is due to the cumulative effect of the BCL-2 family of proteins that act as the gate keepers of the mitochondrial apoptotic pathway. Priming is measured by determining the sensitivity of mitochondria to perturbation by peptides derived from the BH3 domains of pro-apoptotic proteins. Using BH3 profiling, we now have a functional readout that can quantify priming and assess its contribution to drug sensitivity. Here we show that priming affects the sensitivity of acute myeloid leukemia (AML) cell lines to various standard chemotherapeutics, especially topoisomerase II inhibitors. Priming predicts clinical response to conventional induction chemotherapy as well as the long term maintenance of remission in AML patients. Interestingly, the priming of normal hematopoietic stem cells (HSCs) sits at the boundary line between the priming of cured and refractory patient AML. This HSC priming likely defines the therapeutic index since AML that are lower primed than HSCs are often refractory and cannot be cured without transplantation. Additionally, our BH3 profiles revealed that AML cells are more sensitive to BCL-2 antagonism than normal HSCs, which are primarily dependent on MCL-1. Indeed, we were able to kill primary refractory AML cells in vitro with the BCL-2 antagonist ABT-737 at doses that left HSCs unharmed. Cumulatively, these findings show that priming is a major mechanistic determinant of AML response in vitro and in the clinic to standard induction chemotherapy. With the ability to predict outcome, BH3 profiling may offer physicians and patients a promising tool for treatment decision-making.
28
Ma, Leyuan. "Targeting Drug Resistance in Chronic Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/870.
Повний текст джерелаАнотація:
Inhibiting BCR-ABL kinase activity with tyrosine kinase inhibitors (TKIs) has been the frontline therapy for CML. Resistance to TKIs frequently occurs, but the mechanisms remain elusive.
First, to uncover survival pathways involved in TKI resistance in CML, I conducted a genome-wide RNAi screen in human CML cells to identify genes governing cellular sensitivity to the first generation TKI called IM (Gleevec). I identified genes converging on and activating the MEK/ERK pathway through transcriptional up-regulation of PRKCH. Combining IM with a MEK inhibitor synergistically kills TKI-resistant CML cells and CML stem cells.
Next, I performed single cell RNA-seq to compare expression profiles of CML stem cells and hematopoietic stem cells isolated from the same patient. Among the genes that are preferentially expressed in CML stem cells is PIM2, which encodes a pro-survival serine-threonine kinase that phosphorylates and inhibits the pro-apoptotic protein BAD. Inhibiting PIM2 function sensitizes CML stem cells to IM-induced apoptosis and prevents disease relapse in a CML mouse model.
Last, I devised a CRISPR-Cas9 based strategy to perform insertional mutagenesis at a defined genomic location in murine hematopoietic Ba/F3 cells. As proof of principle, we showed its capability to perform unbiased, saturated point mutagenesis in a 9 amino acid region of BCR-ABL encompassing the socalled “gatekeeper” residue, an important determinant of TKI binding. We found that the ranking order of mutations from the screen correlated well with their prevalence in IM-resistant CML patients.
Overall, my findings reveal novel resistance mechanisms in CML and provide alternative therapeutic strategies.
29
Varchol, Karen. "Parental occupational exposures and acute myeloid leukemia in offspring /." The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488203857250743.
Повний текст джерела
30
Valia, Dhvani. "EMERGING NATURAL KILLER CELL IMMUNOTHERAPY FOR ACUTE MYELOID LEUKEMIA." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1561938259242716.
Повний текст джерела
31
Ma, Leyuan. "Targeting Drug Resistance in Chronic Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2011. http://escholarship.umassmed.edu/gsbs_diss/870.
Повний текст джерелаАнотація:
Inhibiting BCR-ABL kinase activity with tyrosine kinase inhibitors (TKIs) has been the frontline therapy for CML. Resistance to TKIs frequently occurs, but the mechanisms remain elusive.
First, to uncover survival pathways involved in TKI resistance in CML, I conducted a genome-wide RNAi screen in human CML cells to identify genes governing cellular sensitivity to the first generation TKI called IM (Gleevec). I identified genes converging on and activating the MEK/ERK pathway through transcriptional up-regulation of PRKCH. Combining IM with a MEK inhibitor synergistically kills TKI-resistant CML cells and CML stem cells.
Next, I performed single cell RNA-seq to compare expression profiles of CML stem cells and hematopoietic stem cells isolated from the same patient. Among the genes that are preferentially expressed in CML stem cells is PIM2, which encodes a pro-survival serine-threonine kinase that phosphorylates and inhibits the pro-apoptotic protein BAD. Inhibiting PIM2 function sensitizes CML stem cells to IM-induced apoptosis and prevents disease relapse in a CML mouse model.
Last, I devised a CRISPR-Cas9 based strategy to perform insertional mutagenesis at a defined genomic location in murine hematopoietic Ba/F3 cells. As proof of principle, we showed its capability to perform unbiased, saturated point mutagenesis in a 9 amino acid region of BCR-ABL encompassing the socalled “gatekeeper” residue, an important determinant of TKI binding. We found that the ranking order of mutations from the screen correlated well with their prevalence in IM-resistant CML patients.
Overall, my findings reveal novel resistance mechanisms in CML and provide alternative therapeutic strategies.
32
Teleanu, Maria-Veronica [Verfasser]. "RUNX1 mutations in acute myeloid leukemia / Maria-Veronica Teleanu." Ulm : Universität Ulm, 2017. http://d-nb.info/1135665141/34.
Повний текст джерела
33
MILOVANOVIC, SARA. "NON-GENETIC MECHANISMS OF CHEMORESISTANCE IN ACUTE MYELOID LEUKEMIA." Doctoral thesis, Università degli Studi di Milano, 2022. https://hdl.handle.net/2434/946408.
Повний текст джерелаАнотація:
Acute Myeloid Leukemia (AML) is the most common type of acute hematological malignancy in adults. 40–60% of patients relapse due to the emergence of cellular resistance to anti- leukemic drugs. Drug resistance in leukemic cells has been associated with intratumoral heterogeneity, among which quiescence, specifically, is considered a key factor for cell survival. Experimental evidence collected both from patients and model systems suggests that relapse is due to rare persistent AML cells which survive chemotherapy. Chemotherapy persistent cells are not yet biologically and molecularly defined. Open questions are whether persistent cells are drug-resistant, what are their cellular and molecular features, as well as their content in leukemic stem cells. My working hypothesis is that chemoresistance in AMLs is associated with specific phenotypic states that characterize rare cell populations found within the pool of quiescent leukemic cells. These cells are selected by chemotherapy and represent the cellular basis of the relapse. To test my hypothesis, I explored transcriptional and functional characteristics of quiescent leukemic cells and tested the effect of chemotherapy. Here, I present two newly established xeno-models of chemoresistant human AMLs that closely recapitulate clinical data. My data show that quiescent cells accumulate over time and quiescent and proliferating cells can switch from one state to another. Notably, quiescent cells are selectively spared by chemotherapy and show resistance to additional rounds of treatment. Finally, quiescent cells appear as the only carrier of tumorigenic capacity in AMLs and are, therefore, deemed essential for leukemia development and, possibly, relapse.
34
Corlazzoli, F. "REGENERATION-ASSOCIATED WNT SIGNALING ACTIVATION IN ACUTE MYELOID LEUKEMIA." Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/169569.
Повний текст джерелаАнотація:
Ample evidence exists in mouse models that acute myeloid leukemia (AML)
develops through stepwise acquisition of collaborating genetic and epigenetic
changes in self-renewing leukemia-initiating cells (LICs) that exhibit a committed
myeloid immunophenotype. Recently, critical questions emerged regarding the
characterization of LICs in the CD34+CD38- fraction and the AC133 antigen (a
glycosylation-dependent epitope of CD133) seems to be one of the markers more
appropriate to enrich for the LICs-containing fraction. The requirement of the
Wnt/β-catenin pathway in the pathogenesis of acute myeloid leukemia (AML) has
recently emerged in mouse models. However, its relationship to genetic programs
promoting retention of self-renewing leukemia stem cells (LSCs) remains elusive.
Hence, the need to identify transcriptional programs involved in the maintenance of
a self-renewing state in LSCs. Given the predominant role of transcription factors
(TFs) function in myeloid leukemia and recent progresses in reprogramming
research for a critical role of TFs in the establishment and maintenance of cellular
phenotypes, here we generated a specially designed transcriptional regulators
(TRs) dataset to interrogate expression microarray data obtained from AC133+
cells in AML patients and healthy donors. Our data suggest that the canonical
Wnt/β-catenin signaling is activated in leukemic human long-term reconstituting
AC133+ restricted cells. In a series of molecular and functional studies we found
that leukemic cells AC133+ synthesize and secrete WNT10B, a hematopoietic
stem cells (HSCs) regenerative-associated molecule, and increase the levels of
dephosphorylated β-catenin. Nevertheless, AML AC133+ cells, in zebrafish
embryos, are able to develop ectopic structures by activating organizer markers
that act downstream of the Wnt pathway. In light of the long-known association
between cancer and chronic tissue injury, and because of the higher homeostatic
range of Wnt/β-catenin signaling occurring during regeneration upon an acute
injury, altogether our data provide compelling evidence that regenerationassociated
Wnt signaling exceeds the homeostatic range in human AML and
affects responsive cells whose renewal is promoted by Wnt pathway activity.
35
RESTELLI, CECILIA. "THE ROLE OF QUIESCENCE IN ACUTE MYELOID LEUKEMIA GROWTH." Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/909748.
Повний текст джерелаАнотація:
Acute myeloid leukemia (AML) is the most common leukemia in adults and its prognosis is usually poor. The main culprit of therapy failure and leukemia relapse is the genomic and biological heterogeneity of the tumor. At biological level, AML is hierarchical organized with leukemia stem cells (LSCs) at the apex. LSCs are a rare cell population able to initiate and sustain leukemia growth and share many features with hematopoietic stem cells (HSCs), including self-renewal capacity and quiescence. Traditional therapies have limited effects on LSCs, mainly due to their quiescent state.
Preliminary data in our group have shown that different leukemia-initiating oncogenes (NPMc+, PML-RARα and MLL-AF9) share the property of enforcing quiescence in HSCs, and that this is critical for the progression and maintenance of the leukemia clone. Underlying molecular mechanisms, however, are unknown.
To this end, we performed an in vivo genetic screening to identify quiescence-related genes that are fundamental for leukemia growth. Among the identified hits, Socs2, Stat1 and Sytl4 silencing prevented AML outgrowth in vivo. Notably, Socs2 and Stat1 interference increased proliferation while preventing the progressive accumulation of quiescent blasts in the growing leukemia.
Interestingly, Socs2 and Stat1 silencing in vitro significantly decreased the clonogenic activity of AML blasts, while having no effects on proliferation, cell cycle distribution or survival, suggesting that the effects of Socs2 and Stat1 were largely dependent on the in vivo leukemia context. scRNAseq analysis of Socs2-interfered blasts showed marked downregulation of genes characterizing the dormant status of quiescent HSCs, suggesting that loss of quiescence in Socs2-interfered blasts may be linked to the loss of their regenerative potential. Since prolonged stress signals are responsible for the disruption of dormancy and self-renewal potential in HSCs, scRNAseq data were analyzed for the activation of the integrated stress response (ISR). Strikingly, we found that ATF4, UPR and autophagic transcriptional programs were increasingly expressed in proliferating blasts, while they were aberrantly activated in both proliferating and cell cycle restricted Socs2-interfered cells. Elevated levels of UPR may act as danger signals, favoring an immune-mediated clearance. Consistently, Socs2-silenced blasts markedly downregulated specific immune check-point molecules, including CD24a, galectin 9 and VISTA, which are involved in the regulation of B cells, T cells, NK cells and macrophages. Notably, activation of the ISR and immune check-point molecules in MA9 blasts resembled the adaptive response of HSCs to oncogene-induced hyperproliferation. Based on these findings, we hypothesized that Socs2 regulates the resolution of the ISR response in hyperproliferating MA9 blasts by allowing cells with activated ISR to enter quiescence and trigger further pathways of ISR resolution, including upregulation of immune check-point molecules. In the absence of Socs2-mediated quiescence, cells maintain a sustained activation of the ISR, downregulate immune check-point molecules and activate immune-mediated cell death.
To preliminarily test this hypothesis, the growth potential of Socs2-interfered blasts was evaluated in immunocompromised mice,where a significant attenuation of the anti-leukemic effect of Socs2 interference was observed. As well, macrophage depletion prolonged disease latency of immunocompetent mice transplanted with Socs2-interfered blasts.
These findings provide preliminary evidence of the existence, in AML blasts, of an adaptive response to hyperproliferation that involves ISR activation, induction of quiescence and immune evasion. Targeting this adaptive response, as by Socs2 interference, may activate potent mechanisms of AML immune clearance.
36
MAREGA, MANUELA. "Molecular mechanisms for the progression of chronic myeloid leukemia." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2010. http://hdl.handle.net/10281/17737.
Повний текст джерелаАнотація:
Chronic myeloid leukaemia (CML) is caused by the BCR-ABL hybrid gene. The molecular mechanisms leading from chronic phase (CP) to blast crisis (BC) are not understood. However, both the presence and the levels of BCR-ABL seem to be important for CML progression. BCR-ABL is under the transcriptional control of BCR promoter. Here we focused on the gene expression control of BCR and BCR-ABL upon myeloid differentiation in healthy donors (HDs), CP and BC patients. As previously reported, BCR-ABL is downregulated during myeloid maturation in CP patients. A similar pattern was detected for BCR (but not for ABL) in CP-CML and in HD, thus suggesting that the two genes may be under a similar transcriptional control. In BC this mechanism is similarly impaired for both BCR-ABL and BCR. These data indicate the presence of an ‘in trans’ deregulated transcription of both BCR and BCR-ABL promoters, associated with CML progression. The results of the luciferase assay indicate that the region comprised between 420 and 900 bp from the coding ATG site is required to achieve a basal transcription level. Previous studies suggest that a putative SP1 binding site could have a role in the basal promoter activity. In fact, an almost complete absence of transcriptional activity was measured in delta1041 and delta1271 constructs, lacking both the main transcription start site and the putative SP1 binding region. We hypothesize that SP1 could be responsible for the basal promoter activity, present in the delta541 and in longer constructs. The ChIP assay confirmed the SP1-binding to the BCR promoter. The presence of 10 additional putative protein binding sites (PBSs), along the BCR promoter is also known from previous works. Six of these putative PBSs are localized in the region between −1443 to −1202 bp, which appears to be critical from in silico studies. In fact, only in presence of a 221 bp region upstream from delta241, a strong luciferase signal could be detected, suggesting that the promoter region between −1443 and −1202 bp from the coding ATG is indeed critical to achieve the highest level of expression.
37
Heaney, Nicholas Benjamin. "Proteasome inhibition in chronic myeloid leukaemia." Thesis, Connect to e-thesis, 2009. http://theses.gla.ac.uk/832/.
Повний текст джерелаАнотація:
Thesis (MD.) - University of Glasgow, 2009.MD. thesis submitted to the Faculty of Medicine, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, 2009. Includes bibliographical references. Print version also available.
38
Ihme, Erika Ruth Susann [Verfasser]. "Characterization of the Leukemia Initiating Cell in Human Acute Myeloid Leukemia / Erika Ruth Susann Ihme." Ulm : Universität Ulm, 2016. http://d-nb.info/1126036323/34.
Повний текст джерела
39
關子祺 and Tsz-ki Kwan. "The detection of BCR-ABL kinase domain mutation in the management of chronic myeloid leukemia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40738358.
Повний текст джерела
40
Kwan, Tsz-ki. "The detection of BCR-ABL kinase domain mutation in the management of chronic myeloid leukemia." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B40738358.
Повний текст джерела
41
Mhadgut, Hemendra M. D., Chandana M. D. Kamireddy, Alok M. D. Sinha, Sakshi M. D. Singal, and Devapiran M. D. Jaishankar. "Innumerable bone lesions: An atypical presentation of Acute Myeloid Leukemia." Digital Commons @ East Tennessee State University, 2021. https://dc.etsu.edu/asrf/2021/presentations/19.
Повний текст джерелаАнотація:
Acute myeloid leukemia(AML) is the most common acute leukemia among adults in the United states with approximately 19,940 people being diagnosed of this disease in 2020 and 11,180 deaths. It is a heterogenous group of malignancy characterized by clonal expansion of blast with myeloid lineage in the bone marrow, peripheral blood and/or other tissues.
Our patient is a 79-year-old male who presented to the hospital with reports of sharp, throbbing low back pain for one month, moderately controlled with pain medications. He reported 5 lb. weight loss with decreased appetite over one month but denied other constitutional symptoms. MRI Lumbar spine revealed multiple foci of marrow signal abnormality compatible with extensive metastatic disease. CT chest, abdomen and pelvis did not show any lesions concerning for primary or metastatic malignancy. CBC revealed normal WBC count, platelet count and hemoglobin level (with macrocytosis, MCV 104.7). Initial work up including Vitamin B12 and folic acid level, TSH, SPEP/IFE, serum light chain ratio and quantitative immunoglobulins were within normal limits. Pathology from a CT guided bone biopsy of the L spine lesion was concerning for high grade myeloid neoplasm. Patient had a bone marrow biopsy done at another hospital which was read as most consistent with acute myeloid leukemia (AML) with monocytic differentiation, with findings of hypocellular marrow, extensive fibrosis with focal areas of large clusters of immature cells, positive for MPO, CD33, CD43 and CD 56, Ki-67 of 60-80%. Cytogenetics showed an abnormal male karyotype with trisomy 8. FISH was negative for other AML or MDS related abnormalities. Given the above findings of AML and advanced age, patient was started on treatment with hypomethylating agent Decitabine along with BCL-2 inhibitor, Venetoclax. A repeat bone marrow biopsy after two cycles of the above regimen revealed progressive disease with extensive fibrosis and 80-90% blast on a core biopsy sample. Due to poor response to above regimen, lack of effective treatment options in older patients with AML and declining functional status, decision was made to pursue best supportive care.
AML usually presents with symptoms of fevers, fatigue, dyspnea or bleeding. Skeletal lesions are usually associated with a diagnosis of multiple myeloma, or other solid organ malignancies and rare in AML. Extra medullary involvement of AML is known to happen in 2.5%-9% of patients and is termed as Myeloid Sarcoma. Due to the low incidence, prospective study data is limited. This entity is treated similarly to AML, depending on risk stratification by cytogenetics, age and targetable mutations which also govern its prognosis. This case highlights the importance of increased awareness and high index of suspicion among medical providers regarding this atypical presentation of AML since if missed or misdiagnosed could delay treatment and lead to poor outcomes.
42
Dorrance, Adrienne M. "The role of the partial tandem duplication of the MLL (MLL PTD) in leukemogenesis." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1203712889.
Повний текст джерела
43
Deshpande, Aniruddha. "Characterisation of the Leukemic Stem Cell in a Murine Model of CALM/AF10 Positive Myeloid Leukemia." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-57555.
Повний текст джерела
44
Mansurov, Alay, Sakshi Singal Singal, Sara Masood, and Devapiran Jaishankar. "Myeloid Sarcoma." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/14.
Повний текст джерелаАнотація:
Acute Myeloid Leukemia (AML) is a potentially fatal disease, more common in an elderly population. The American Cancer Society estimates 21,450 new cases of AML and 10,920 deaths from AML in the United States in 2019. This malignancy originating in the Bone Marrow (BM), usually presents with peripheral blood (PB) abnormalities. Rarely, AML, particularly monoblastic variants can present with extramedullary disease. Here we describe a case of AML presenting with diffuse lymphadenopathy and a biopsy revealing myeloid sarcoma. A 53 years old male developed diffuse lymphadenopathy. Failure of outpatient empiric antibiotic treatment prompted right cervical lymph node biopsy. Lymph node architecture was distorted by the presence of malignant monocytic myeloid cells. Both the peripheral blood and bone marrow were involved by AML with monocytic features. The monoblasts count was 14% in PB and 24% in BM and the promonocyte count was 12% in PB and 26% in BM. Complete Blood Count showed total white blood cell count of 31,700, hemoglobin 11.8, monocytes 22.5% and platelets 122,000. Flow cytometry of the bone marrow demonstrated a blast population with positive expression of cMPO, CD33, CD13, CD11b, HLA-DR, CD64, CD14 and CD4; and negative for CD34, CD117, nTdT, cCD3, cCD79a. Fluorescence in situ hybridization study was positive for MLL gene rearrangement. Molecular study was positive for IDH1 mutation, and negative for IDH2, RUNX1, FLT3 mutations. Further laboratory analysis was significant for lactate dehydrogenase 346, uric acid 8.6, prothrombin time 13.6, INR 1.2, partial thromboplastin time 33.5 and fibrinogen 293. Computed tomography of chest, abdomen, pelvis with contrast revealed extensive adenopathy with enlarged bilateral supraclavicular, bilateral axillary, mediastinal, bilateral hilar, upper abdominal, periaortic retroperitoneal, pelvic and inguinal lymph nodes. Hepatosplenomegaly was also reported. The term Myeloid Sarcoma (MS) is used when leukemic cells are present outside the bone marrow and peripheral blood. MS tends to oocur more commonly in middle aged males (male-to-female ratio, 2:1, median age, 56 years). The Mayo Clinic Experience of 96 cases demonstrated 27% of patients had no bone marrow involvement, and 69% of patients had primary bone marrow disease. Extramedullary involvement can occur prior to, simultaneously, or after bone marrow involvement. Just as in our case this is an important feature for clinicians to remember so that they may recognize this rare entity early.
45
Nagura, Eiichi, Saburo Minami, Koichiro Nagata, Yoshihisa Morishita, Hideo Takeyama, Hiroshi Sao, Hisamitsu/ Suzuki, et al. "Acute myeloid leukemia in the elderly : 159 Nagoya case studies." Nagoya University School of Medicine, 1999. http://hdl.handle.net/2237/5348.
Повний текст джерела
46
Eriksson, Anna. "Studies of New Signal Transduction Modulators in Acute Myeloid Leukemia." Doctoral thesis, Uppsala universitet, Cancerfarmakologi och beräkningsmedicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-182440.
Повний текст джерелаАнотація:
Acute myeloid leukemia (AML) is a life-threatening malignant disorder with dismal prognosis. AML is characterized by frequent genetic changes involving tyrosine kinases, normally acting as important mediators in many basic cellular processes. Due to the overexpression and frequent mutations of the FMS-like receptor tyrosine kinase 3 (FLT3) in AML, this tyrosine kinase receptor has become one of the most sought after targets in AML drug development. In this thesis, we have used a combination of high-throughput screens, direct target interaction assays and sequential cellular screens, including primary patient samples, as an approach to discover new targeted therapies. Gefitinib, a previously known inhibitor of epidermal growth factor receptor and the two novel tyrosine kinase inhibitors AKN-032 and AKN-028, have been identified as compounds with cytotoxic activity in AML. AKN-028 is a potent inhibitor of FLT3 with an IC50 value of 6 nM in an enzyme assay, but also displaying in vitro activity in a variety of primary AML samples, irrespective of FLT3 mutation status or quantitative FLT3 expression. AKN-028 shows a sequence dependent in vitro synergy when combined with standard cytotoxic agents cytarabine or daunorubicin, with better efficacy when cells are exposed to standard chemotherapy simultaneously or for 24 hours prior to adding AKN-028. Antagonism is observed when cells are pre-treated with AKN-028, possibly explained by the cell cycle arrest induced by the compound. In vivo cytotoxic activity and good oral bioavailability have made AKN-028 a candidate drug for clinical studies and the compound is presently investigated in an international two-part multicenter phase I/II study. Results from microarray studies performed to further elucidate the mechanism of action of AKN-028, revealed significantly altered gene expression induced by AKN-028 in both AML cell lines and in primary AML cells, with an enrichment of the Myc pathway among the downregulated genes. Furthermore, tyrosine kinase activity profiling shows a dose-dependent kinase inhibition by AKN-028 in all AML samples tested. Interestingly, cells with a high overall kinase activity were more sensitive to AKN-028. Provided conformation in a larger set of samples, kinase activity profiling may give useful information in individualizing treatment of patients with AML.
47
Ho, Siu-ki, and 何肇騏. "DNA methylation patterns in t(8;21) acute myeloid leukemia patients." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47151389.
Повний текст джерелаАнотація:
Acute myeloid leukemia (AML) is a heterogeneous disease both clinically and
biologically. Approximately 55% of AML harbour karyotypic changes, and one of the most common chromosomal aberrations is the t(8;21)(q22;q22), which leads to the AML1-ETO fusion protein. Previous studies have found that this fusion protein recruits the N-CoR/mSin3A/HDAC complex, thereby acts as a transcriptional repressor. Recently, DNA methylation array studies have shown that DNA methylation patterns can stratify AML cases into different subgroups, and some of these correspond to certain chromosomal abnormalities, such as the t(8;21). These findings suggest a possible link between the fusion transcript AML1-ETO and epigenetic modifications. Additionally, c-kit mutations have emerged as an important disease modifier in the t(8;21) AML and are correlated with poor overall survival and event free survival in patients with t(8;21) AML. We therefore sought to investigate whether there are different DNA methylation patterns in t(8;21) AML with or without c-kit mutations. In our series, 52.2% of the t(8;21) AMLs harbored c-kit mutations, which were correlated with poor event free survival. We next performed pyrosequencing on a selected panel of genes and pinpointed the THBS4 and PAWR genes as hypermethylated in their promoter CpG islands in 86.4% and 59.1% of the t(8;21) AML patients, respectively. These data suggest that THBS4 and PAWR may be important in the pathogenesis of t(8;21) AML.published_or_final_version
Pathology
Master
Master of Philosophy
48
Han, Ho-chun, and 韓浩俊. "JAK-STAT pathway as potential target of acute myeloid leukemia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B50534208.
Повний текст джерелаАнотація:
Acute myeloid leukemia (AML) is a group of heterogeneous diseases characterized by an abnormal increase in myeloblasts. Despite intensive chemotherapy and allogeneic bone marrow transplantation, the treatment outcome of AML remains unsatisfactory, with a cure rate of only about 30%. Therefore, novel therapeutic strategies targeting the pathogenetic pathways of leukemia initiation and progression are needed. Using intracellular phospho-flow analysis with normal bone marrow as reference, we detected an increase in phosphorylated-STAT5 (pSTAT5) in three leukemic cell lines (K562, KG-1 and ML-2) and 15 primary AML samples. Treatment with specific JAK2 inhibitor TG101209 and JAK2/3 inhibitor AG490 significantly reduced pSTAT5 level and leukemia cell growth associated with an increase in apoptosis and decrease in cellular proliferation. The clonogenic activities of these leukemia cell lines were also significantly reduced. Furthermore, treatment with these inhibitors in K562 and KG-1 also significantly reduced the WNT signaling activity, as enumerated by the TOP/FLASH luciferase assay. In addition, genes associated with oncogenic potential and anti-apoptosis were significantly reduced, consistent with the pathogenetic role of JAK-STAT pathway.
In summary, the present study highlighted the importance of the JAK2-STAT5 signaling pathway in sustaining AML. The results may open up a new avenue whereby new therapeutic strategies targeting AML can be designed.published_or_final_version
Medicine
Master
Master of Philosophy
49
Man, Cheuk-him, and 文卓謙. "Mechanism of sorafenib resistance in FLT3-ITD⁺ acute myeloid leukemia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193461.
Повний текст джерелаАнотація:
Acute myeloid leukemia (AML) is a group of heterogeneous diseases characterized by an abnormal increase in myeloblasts in circulation and/or bone marrow. Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene occurs in about 30% of AML and is associated with an inferior prognosis. Tyrosine kinase domain (TKD) mutations occur in about 5% with uncertain prognostic significance. Intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) are the mainstays of treatment. However these approaches have reached a deadlock with a cure rate of 30-40%. Targeting FLT3 in AML with multi-tyrosine-kinase inhibitors has been evaluated in Phase II/III clinical trials. Despite an initial clearance of myeloblasts, the leukemia invariably progresses despite continuous treatment. The mechanisms of drug resistance and leukemia progression, hence the effective therapeutic strategies are currently unknown, limiting its clinical application.
These issues were addressed in the present study. In the first part, 13 patients with chemo-refractory or relapsed FLT3-ITD+ AML received sorafenib 200-400 mg twice daily of whom 12 patients achieved clearance or near clearance of bone marrow blasts after a median of 27 days (range 21-84 days). There was evidence of myeloid differentiation of the leukemia blasts at remission. Leukemia progression occurred in 9 patients after a median of 72 days (range 54-287 days) and in 4 out of 6 patients it was dominated by clones carrying double FLT3-ITD and -TKD mutations. Microarray studies comparing myeloblasts before sorafenib treatment (sorafenib naïve) and at subsequent progression (sorafenib resistant) demonstrated up-regulation of 64 genes including ALDH1A1, JAK3 and TESC whose functions were unknown in AML. Transplantation of sorafenib naïve and resistant myeloblasts into NOD/SCID mice recapitulated their clinical behavior when the animals were treated with sorafenib. Both ITD and TKD mutations at D835 were identified in leukemia initiating cells (LICs) from sorafenib naïve samples. These results suggested that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations.
In the second part, the gene encoding tescalcin (TESC), that was up-regulated at sorafenib resistance and was known to activate a sodium/hydrogen exchange (NHE1), was evaluated to examine its link with TKI resistance. TESC was highly expressed in FLT3-ITD+ AML cell lines MOLM-13 and MV4-11 and its knock-down by siRNA lowered intracellular pH and induced apoptosis. The results were recapitulated by treatment with a NHE1 inhibitor, 5-(N,N-Hexamethylene)amiloride (HMA). Induction of sorafenib resistance in MOLM-13 cell line (MOLM-13-RE) significantly increased its sensitivity to HMA. HMA treatment of MOLM-13 and MV4-11 as well as primary FLT3-ITD+ AML cells significantly reduced leukemia initiation in NOD/SCID mouse xenotransplantation. Normal CD34+ cells engraftment was not affected. HMA treatment significantly enhanced suppression of FLT3 signaling by sorafenib even in sorafenib resistant cell lines. These observations provided novel information about the pathogenetic role of TESC-NHE1-pHi in sorafenib resistance in AML.
In conclusion, the information derived from the present study has provided mechanistic insights to the emergence of drug resistance during sorafenib treatment and important guide for future therapeutic strategies targeting FLT3-ITD+ AML.published_or_final_version
Medicine
Doctoral
Doctor of Philosophy
50
Fontana, Maria Chiara <1990>. "Exploiting genomic instability in Acute Myeloid Leukemia: when TP53 fails." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2019. http://amsdottorato.unibo.it/9071/1/PhDTHESIS_Fontana_final.pdf.
Повний текст джерелаАнотація:
Acute myeloid leukemia (AML) is a myeloid neoplasm with a heterogenic genomic background and a poor prognosis. The main aims of this thesis are to deepen the pathogenic mechanism of genomic instability (1) and drug-resistance (2) p53-related, in order to identify new targets and biomarker of response through genomic and in vitro approaches.
(1) A peculiar mechanism of genomic instability is chromothripsis, a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. Chromothripsis was detected with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had a poor overall survival, higher age (p = .002), ELN2107 high risk (HR), lower white blood cell count, TP53 loss and/or mutations while FLT3 and NPM1 mutations were mutually exclusive with chromothripsis. Chromothripsis-positive patients presented the hallmarks of chromosome instability [TP53 alteration, 5q deletion, a higher mean of copy number alteration, complex karyotype, alterations in DNA repair and cell cycle]. CBA and FISH showed that chromothripsis was associated with marker, derivative and ring chromosomes.
(2) PPM1D is a promising oncogene coding for “Wild type p53-Inducible Phosphatase 1” (WIP1) which negatively regulates p53 and several proteins involved in the DNA damage response. A recent study has demonstrated that PPM1D inhibition by GSK2830371 reverses chemotherapy resistance to Cytarabine. The aim of this work is to investigate whether the inhibition of WIP1 by GSK2830371 could increase the sensitivity to MDM2 inhibitor Nutlin-3a to obtain a novel therapeutic strategy for AML patients restoring p53 activity. Our study showed that in vitro pharmacological inhibition of WIP1 by GSK2830371 potentiates the sensitivity to Nutlin-3a, a MDM2 inhibitor, in AML cells by stabilizing the activity of p53 by activating apoptosis and other p53-downstream genes and pathways, as confirmed by gene expression profile and western blot analyses of treated AML cells.