Academic literature on the topic 'BCR-ABL like'
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Journal articles on the topic "BCR-ABL like"
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Gross, Alec W., Xiaowu Zhang, and Ruibao Ren. "Bcr-Abl with an SH3 Deletion Retains the Ability To Induce a Myeloproliferative Disease in Mice, yet c-Abl Activated by an SH3 Deletion Induces Only Lymphoid Malignancy." Molecular and Cellular Biology 19, no. 10 (October 1, 1999): 6918–28. http://dx.doi.org/10.1128/mcb.19.10.6918.
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ABSTRACT The bcr-abl oncogene plays a critical role in the pathogenesis of chronic myelogenous leukemia (CML). The fusion of Bcr sequences to Abl constitutively activates the Abl protein tyrosine kinase. We have recently shown that expression of Bcr-Abl in bone marrow cells by retroviral transduction efficiently induces in mice a myeloproliferative disease resembling human CML and that Abl kinase activity is essential for Bcr-Abl to induce a CML-like myeloproliferative disease. However, it is not known if activation of the Abl kinase alone is sufficient to induce a myeloproliferative disease. In this study, we examined the role of the Abl SH3 domain of Bcr-Abl in induction of myeloproliferative disease and tested whether c-Abl activated by SH3 deletion can induce a CML-like disease. We found that Bcr-Abl with an Abl SH3 deletion still induced a CML-like disease in mice. In contrast, c-Abl activated by SH3 deletion induced only lymphoid malignancies in mice and did not stimulate the growth of myeloid colonies from 5-fluorouracil-treated bone marrow cells in vitro. These results indicate that Bcr sequences in Bcr-Abl play additional roles in inducing myeloproliferative disease beyond simply activating the Abl kinase domain and that functions of the Abl SH3 domain are either not required or redundant in Bcr-Abl-induced myeloproliferative disease. The results also suggest that the type of hematological neoplasm induced by an abl oncogene is influenced not only by what type of hematopoietic cells the oncogene is targeted into but also by the intrinsic oncogenic properties of the particular abl oncogene. In addition, we found that ΔSH3 c-Abl induced less activation of Akt and STAT5 than did Bcr-Abl, suggesting that activation of these pathways plays a critical role in inducing a CML-like disease.
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Cross, Nick. "BCR-ABL Negative CML-Like Disorder." Clinical Lymphoma Myeloma and Leukemia 17 (September 2017): S107—S108. http://dx.doi.org/10.1016/j.clml.2017.08.052.
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He, Yiping, Jason A. Wertheim, Lanwei Xu, Juli P. Miller, Fredrick G. Karnell, John K. Choi, Ruibao Ren, and Warren S. Pear. "The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia–like disease by bcr/abl." Blood 99, no. 8 (April 15, 2002): 2957–68. http://dx.doi.org/10.1182/blood.v99.8.2957.
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Abstract The bcr/abl fusion in chronic myelogenous leukemia (CML) creates a chimeric tyrosine kinase with dramatically different properties than intact c-abl. In P210 bcr/abl, the bcr portion includes a coiled-coil oligomerization domain (amino acids 1-63) and a grb2-binding site at tyrosine 177 (Tyr177) that are critical for fibroblast transformation, but give variable results in other cell lines. To investigate the role of the coiled-coil domain and Tyr177 in promoting CML, 4 P210 bcr/abl-derived mutants containing different bcr domains fused to abl were constructed. All 4 mutants, Δ(1-63) bcr/abl, (1-63) bcr/abl, Tyr177Phe bcr/abl, and (1-210) bcr/abl exhibited elevated tyrosine kinase activity and conferred factor-independent growth in cell lines. In contrast, differences in the transforming potential of the 4 mutants occurred in our mouse model, in which all mice receiving P210 bcr/abl-expressing bone marrow cells exclusively develop a myeloproliferative disease (MPD) resembling human CML. Of the 4 mutants assayed, only 1-210 bcr/abl, containing both the coiled-coil domain and Tyr177, induced MPD. Unlike full-length P210, this mutant also caused a simultaneous B-cell acute lymphocytic leukemia (ALL). The other 3 mutants, (1-63) bcr/abl, Tyr177Phe bcr/abl, and Δ(1-63) bcr/abl, failed to induce an MPD but instead caused T-cell ALL. These results show that both the bcr coiled-coil domain and Tyr177 are required for MPD induction by bcr/abl and provide the basis for investigating downstream signaling pathways that lead to CML.
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Hao, Sheryl X., and Ruibao Ren. "Expression of Interferon Consensus Sequence Binding Protein (ICSBP) Is Downregulated in Bcr-Abl-Induced Murine Chronic Myelogenous Leukemia-Like Disease, and Forced Coexpression of ICSBP Inhibits Bcr-Abl-Induced Myeloproliferative Disorder." Molecular and Cellular Biology 20, no. 4 (February 15, 2000): 1149–61. http://dx.doi.org/10.1128/mcb.20.4.1149-1161.2000.
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ABSTRACT Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of a hematopoietic stem cell. The majority of cases of CML are associated with the (9;22) chromosome translocation that generates thebcr-abl chimeric gene. Alpha interferon (IFN-α) treatment induces hematological remission and prolongs life in 75% of CML patients in the chronic phase. It has been shown that mice deficient in interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor family, manifest a CML-like syndrome. We have shown that expression of Bcr-Abl in bone marrow (BM) cells from 5-fluorouracil (5-FU)-treated mice by retroviral transduction efficiently induces a myeloproliferative disease in mice resembling human CML. To directly test whether icsbp can function as a tumor suppressor gene, we examined the effect of ICSBP on Bcr-Abl-induced CML-like disease using this murine model for CML. We found that expression of the ICSBP protein was significantly decreased in Bcr-Abl-induced CML-like disease. Forced coexpression of ICSBP inhibited the Bcr-Abl-induced colony formation of BM cells from 5-FU-treated mice in vitro and Bcr-Abl-induced CML-like disease in vivo. Interestingly, coexpression of ICSBP and Bcr-Abl induced a transient B-lymphoproliferative disorder in the murine model of Bcr-Abl-induced CML-like disease. Overexpression of ICSBP consistently promotes rather than inhibits Bcr-Abl-induced B lymphoproliferation in a murine model where BM cells from non-5-FU-treated donors were used, indicating that ICSBP has a specific antitumor activity toward myeloid neoplasms. We also found that overexpression of ICSBP negatively regulated normal hematopoiesis. These data provide direct evidence that ICSBP can act as a tumor suppressor that regulates normal and neoplastic proliferation of hematopoietic cells.
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Zheng, Xiaomin, Saskia Güller, Gesine Bug, Bithia Grace, Roxana Bistrian, Dieter Hoelzer, Oliver G. Ottmann, Reinhard Henschler, and Martin Ruthardt. "The Reciprocal t(9;22)-Translocation Products ABL/BCR Have Leukemogenic Potential Independently from BCR/ABL." Blood 104, no. 11 (November 16, 2004): 214. http://dx.doi.org/10.1182/blood.v104.11.214.214.
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Abstract In 95% of chronic myeloid leukemia (CML) and in 25% of acute lymphatic leukemia (ALL) the t(9;22) translocation fuses the bcr gene on chromosome 22 to the abl gene on chromosome 9 and vice versa. On 22+ the different breakpoints leads to the formation of two different major fusion genes: the major breakpoint (M-bcr) related to CML and the minor (m-bcr) related to ALL. The chimaeric fusion gene on 22+ (Philadelphia-chromosome) encodes for the BCR/ABL protein, the p210(BCR/ABL) in CML and the p185(BCR/ABL) in Ph+ALL. The fusion gene on 9+ encodes for the reciprocal ABL/BCR proteins, the p40(ABL/BCR) in CML and the p96(ABL/BCR) in Ph+ALL. The respective ABL/BCR transcripts are detectable in 65% of CML and 100% of Ph+ ALL patients. The ABL/BCRs are BCR mutants and thus N-terminally truncated Rho-guanine-nucleotide exchange factors (Rho-GEF’s). It is known that the N-terminal truncation can confer transformation potential to Rho-GEFs, such as NET-1. In addition, both ABL/BCRs, like wt BCR, contain a C-terminal Rac-GTPase activating protein (GAP)-domain. CML-associated ABL/BCR (p96(ABL/BCR)) differs from the Ph+ ALL-associated p40(ABL/BCR) in that that it misses the ‘dbl homology domain’(DH domains) of potential oncogenic function. Hence it seems that Ph+ALL blasts, in contrast to CML-blasts, express, as a consequence of t(9;22) translocation, two oncogenic fusion proteins, the p185(BCR-ABL) as well as the p40(ABL/BCR) protein. Actually nothing is known about the contribution of the reciprocal t(9;22) translocation products to the CML- and the ALL-phenotype. Thus we studied the phenotype induced by the ABL/BCRs in hemopoietic progenitors. Here we report that both ABL/BCRs i) lost the capacity of wt BCR to suppress the activation of RAC by its Rac-GAP domain, but did not influence the activation status of Rho or cdc42; ii) as a consequence of the deregulation of Rac the cytoskeleton modelling by BCR (Filopodia - cdc42-like phenotype) was altered in p40(ABL/BCR)- and p96(ABL/BCR)-expressing fibroblasts (stress fibers - Rho-like phenotype and “microspikes”, respectively); iii) the increase of migration of BCR-expressing 32D cells into a stroma cell-spheroid model was reverted in p40(ABL/BCR)- and p96(ABL/BCR)-expressing 32D cells; iv) adhesion to TNFalpha activated endothelial cell layer in the “flow chamber” was increased in BCR-positive 32D cells but not in p40(ABL/BCR)- and p96(ABL/BCR)-positive cells. Regarding their leukemogenic potential we showed that i) both ABL/BCRs, in contrast to wt BCR, activated RAS; ii) both ABL/BCRs were unable to transform fibroblasts and to render Ba/F3 cells factor-independent. iii) p96(ABL/BCR) increased the replating efficiency of Sca1+/lin- hemopoietic stem cells (HSC) by selecting a population of immature HSC exclusively expressing c-kit and Sca-1 more strongly than p40(ABL/BCR); iv.) both ABL/BCR blocked the myeloid differentiation of HSC v) the inoculation of p96(ABL/BCR)- or p40(ABL/BCR)-expressing HSC into lethally irradiated recipient mice led in the 40% and 60% of the cases, respectively, to a clinical picture of either acute leukemia or myeloproliferative syndrome within 2–9 months. These data show for the first time that the t(9;22) leads to two leukemogenic fusion proteins - the BCR/ABL and the ABL/BCR - in CML as well as in Ph+ALL, which might represent an additional target for molecular therapy approaches.
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Million, Ryan P., and Richard A. Van Etten. "The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase." Blood 96, no. 2 (July 15, 2000): 664–70. http://dx.doi.org/10.1182/blood.v96.2.664.014k52_664_670.
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The BCR/ABL oncogene results from a balanced translocation between chromosomes 9 and 22 and is found in patients with chronic myeloid leukemia (CML) and in some patients with acute B-lymphoid leukemia. The Bcr/Abl fusion protein is a constitutively active tyrosine kinase that stimulates several intracellular signaling pathways, including activation of Ras through direct binding of the SH2-containing adapter protein Grb2 to Bcr tyrosine 177. A tyrosine-to-phenylalanine mutation (Y177F) at this site blocks the co-association of Bcr/Abl and Grb2 in vivo and impairs focus formation by Bcr/Abl in fibroblasts. However, the Bcr/Abl Y177F mutant can transform hematopoietic cell lines and primary bone marrow cells in vitro, so the importance of the Bcr/Abl–Grb2 interaction to myeloid and lymphoid leukemogenesis in vivo is unclear. We have recently demonstrated the efficient induction of CML-like myeloproliferative disease by BCR/ABL in a murine bone marrow transduction/transplantation model system. The Y177F mutation greatly attenuates the myeloproliferative disease induced by BCR/ABL, with mice developing B- and T-lymphoid leukemias of longer latency. In addition, the v-abl oncogene of Abelson murine leukemia virus, whose protein product lacks interaction with Grb2, is completely defective for the induction of CML-like disease. These results suggest that direct binding of Grb2 is required for the efficient induction of CML-like myeloproliferative disease by oncogenic Abl proteins.
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Million, Ryan P., and Richard A. Van Etten. "The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase." Blood 96, no. 2 (July 15, 2000): 664–70. http://dx.doi.org/10.1182/blood.v96.2.664.
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Abstract The BCR/ABL oncogene results from a balanced translocation between chromosomes 9 and 22 and is found in patients with chronic myeloid leukemia (CML) and in some patients with acute B-lymphoid leukemia. The Bcr/Abl fusion protein is a constitutively active tyrosine kinase that stimulates several intracellular signaling pathways, including activation of Ras through direct binding of the SH2-containing adapter protein Grb2 to Bcr tyrosine 177. A tyrosine-to-phenylalanine mutation (Y177F) at this site blocks the co-association of Bcr/Abl and Grb2 in vivo and impairs focus formation by Bcr/Abl in fibroblasts. However, the Bcr/Abl Y177F mutant can transform hematopoietic cell lines and primary bone marrow cells in vitro, so the importance of the Bcr/Abl–Grb2 interaction to myeloid and lymphoid leukemogenesis in vivo is unclear. We have recently demonstrated the efficient induction of CML-like myeloproliferative disease by BCR/ABL in a murine bone marrow transduction/transplantation model system. The Y177F mutation greatly attenuates the myeloproliferative disease induced by BCR/ABL, with mice developing B- and T-lymphoid leukemias of longer latency. In addition, the v-abl oncogene of Abelson murine leukemia virus, whose protein product lacks interaction with Grb2, is completely defective for the induction of CML-like disease. These results suggest that direct binding of Grb2 is required for the efficient induction of CML-like myeloproliferative disease by oncogenic Abl proteins.
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Albers, Corinna, Anna L. Illert, Cornelius Miething, Christian Peschel, and Justus Duyster. "Grb10 Mediated Akt Activation Is Required for Induction of CML Like Myeloproliferative Disease in Mice by BCR-ABL." Blood 110, no. 11 (November 16, 2007): 1012. http://dx.doi.org/10.1182/blood.v110.11.1012.1012.
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Abstract Chronic myelogenous leukaemia (CML) results from the neoplastic transformation of hematopoietic stem cells (HSC) and is characterized by a chromosomal translocation t(9;22)(q34;q11). This aberration leads to the expression of the oncogenic tyrosine kinase BCR-ABL, which mediates signals for proliferation, transformation and anti-apoptosis via various signalling pathways. Grb10, a member of the growth factor bound proteins, is known to bind activated tyrosine kinases like BCR-ABL and might be involved in the activation of the Akt signalling pathway. Here we report the impact of Grb10 for BCR-ABL mediated transformation. We exerted a siRNA based approach in combination with a murine bone marrow transplantation model. To this end we designed a MSCV based retrovirus encoding both a Grb10 microRNA and the BCR-ABL oncogene on a single construct. This approach ensured knockdowns of more than 90% in every BCR-ABL transformed cell. Methylcellulose assays demonstrated that bone marrow coexpressing Grb10 microRNA and BCR-ABL had a 4-fold decreased colony forming ability compared to control cells. We then transduced bone marrow (BM) with retrovirus coexpressing Grb10 microRNA and p185 BCR-ABL and transplanted lethally irradiated recipient Balb/C mice. The onset and progression of leukaemia was significantly delayed in mice transplanted with Grb10 microRNA and BCR-ABL compared with the BCR-ABL transduced control microRNA group. However, we were not able to completely avoid the development of leukaemia by Grb10 knockdown. Mice transplanted with the Grb10 knockdown construct showed a delayed lymphoblastic disease, positive for B220, whereas the control group developed a rapid myeloproliferative disease, characterized by CD11b and Gr-1. In vitro analysis of BaF/3 and 32D cells showed that Grb10 knockdown in combination with BCR-ABL expression leads to a reduced phosphorylation of Akt. Taken together our data demonstrate that Grb10 is required for the development of a myeloproliferative disease by BCR-ABL in mice. Hereby, Grb10 seems to be critical for the BCR-ABL induced activation of the Akt pathway. In addition, this study describes a novel approach to express an oncogene and a microRNA using a single retroviral construct. This tool can be used to systematically screen for drugable signalling targets involved in oncogenesis.
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Mohi, M. Golam, Wayne W. Chan, Shaoguang Li, Benjamin Neel, and Richard A. Van Etten. "Distinct Gab2-Mediated Signaling Pathways Are Essential for Myeloid or Lymphoid Transformation and Leukemogenesis by BCR-ABL." Blood 112, no. 11 (November 16, 2008): 570. http://dx.doi.org/10.1182/blood.v112.11.570.570.
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Abstract The BCR-ABL oncogene encodes an activated fusion tyrosine kinase that causes chronic myelogenous leukemia (CML) and B-lymphoid acute lymphoblastic leukemia (B-ALL) in humans. An autophosphorylation site at Tyr 177 of BCR-ABL recruits Grb2 via its SH2 domain, and is required for efficient induction of CML-like myeloproliferative disease by BCR-ABL in a mouse BM retroviral transduction/transplantation model. We showed previously (Sattler et al., Cancer Cell2002;1:479) that the scaffolding/adapter protein Gab2 is recruited to Y177 of BCR-ABL via a Grb2/Gab2 complex, and in vitro transformation of primary myeloid and lymphoid progenitors by BCR-ABL was impaired in bone marrow from mice with homozygous null mutations in the Gab2 gene (Gab2−/− mice), coincident with decreased activation of the ERK and Akt signaling pathways. Here, we demonstrate an essential requirement for Gab2 in myeloid and lymphoid leukemogenesis by BCRABL. Whereas recipients of BCR-ABL-transduced Gab2+/+ BM develop fatal CML-like myeloproliferative disease within 4 weeks of transplantation, recipients of BCR-ABLtransduced Gab2−/− BM fail to develop CML but succumb after a long latent period to T-cell acute lymphoblastic leukemia, phenocopying the disease induced by the BCR-ABL Y177F mutant. These results suggest that the Y177F and Gab2 mutations have an epistatic relationship, and that the critical transforming signals from Tyr177 of BCR-ABL are transmitted through Gab2. Co-expression of Gab2 with BCR-ABL in Gab2−/− BM restored efficient induction of CML-like leukemia, but mutants of Gab2 that lacked either the pleckstrin homology domain or Tyr binding sites for the SH2 domains of the downstream Gab2 effector molecules SHP2 or p85 PI3K failed to rescue myeloid leukemogenesis by BCR-ABL, although the mutant Gab2 proteins were expressed in circulating myeloid cells. Gab2 deficiency attenuated B-lymphoid transformation by BCR-ABL in vitro, and significantly prolonged the latency of B-ALL induced by BCR-ABL in mice. In contrast to CML, induction of B-ALL in Gab2−/− BM was rescued by either WT Gab2 or the Gab2 mutant defective in p85 binding. These results demonstrate that BCR-ABL absolutely requires signaling via Gab2 to both SHP2 and PI3K to cause CML, while a Gab2-SHP2 signaling pathway contributes to the pathogenesis of BCR-ABL+ B-ALL.
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Albers, Corinna, Anna Lena Illert, Cornelius Miething, Christian Peschel, and Justus Duyster. "Raf1 Is Required for Induction of a Bcr-Abl Positive CML Like Myeloproliferative Disease in Mice." Blood 112, no. 11 (November 16, 2008): 3207. http://dx.doi.org/10.1182/blood.v112.11.3207.3207.
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Abstract Introduction: Chronic myelogenous leukemia (CML) results from neoplastic transformation of hematopoietic stem cells (HSC), characterized by a chromosomal translocation t(9;22)(q34;q11). This aberration leads to the expression of the oncogenic tyrosine kinase Bcr-Abl, which mediates signals for proliferation, transformation and anti-apoptosis via various different pathways including the Raf/MEK/ERK cascade. The cytoplasmic protein Raf1 is a key molecule within this cascade. Recent studies have revealed an additional function of the Raf-1 kinase that is independent of the activation of the MAPK cascade and whose effect is to increase resistance to apoptosis. Therefore Raf1 is an interesting target for molecular therapies and more effective Raf1 inhibitors have recently been developed by the pharmaceutical industry. Here we report the impact of Raf1 signalling for Bcr-Abl mediated transformation. Methods: We exerted a siRNA based approach in combination with a murine bone marrow transplantation model. To this end we designed a MSCV based retrovirus encoding both the Raf1 microRNA and the Bcr-Abl oncogene on a single construct. This approach ensured knockdowns of more than 90% of Raf1 in every Bcr-Abl transformed cell. Results: Methylcellulose assays demonstrated that bone marrow coexpressing Raf1 microRNA and Bcr-Abl had a 2 fold decreased colony forming ability compared to control cells. We then transduced bone marrow (BM) with retrovirus coexpressing Raf1 microRNA and p185 Bcr-Abl and transplanted lethally irradiated recipient Balb/C mice. The onset and progression of leukemia was significantly delayed in mice transplanted with Raf1 microRNA and Bcr-Abl compared with the Bcr- Abl transduced control microRNA group. Raf1 knockdown mice showed only a moderate rise of white blood cell (WBC) counts and prolonged overall survival (median survival 39 ± 7.1 days) in comparison to control mice (23.3 ± 2.4 days). However, we were not able to completely avoid the development of leukemia by Raf1 knockdown. Conclusion: Taken together our data demonstrate that Raf1 is important for the development of a myeloproliferative disease by Bcr-Abl in mice. Therefore Raf1 inhibition in combination with Bcr-Abl kinase inhibition depicts an interesting approach towards eradication of Bcr- Abl positive leukemia. In addition, this study describes a novel and versatile approach to express an oncogene and a microRNA using a single retroviral construct. Thus this powerful tool can be used to systematically screen drugable signalling targets involved in oncogenesis.
Dissertations / Theses on the topic "BCR-ABL like"
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Drivet, Elsa. "Etude préclinique personnalisée d'une translocation rare T(1 ; 9)(Q24 ; Q34) "PH-LIKE" et perspectives d'optimisation des traitements contre les LAL-B de mauvais pronostic." Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0664.
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La translocation t(1;9)(q24 ;q34), qui engendre la protéine de fusion RCSD1-ABL1, a été identifiés dans des cas de LAL de mauvais pronostic. Les propriétés oncogéniques du partenaire RCSD1, sa structure et son rôle dans l’activité et la signalisation de RCSD1-ABL1 restent inconnus. Nous avons récemment rapporté le cas d’une LAL-B t(1;9)(q24 ;q34) montrant une résistance à un grand nombre d’ITK, mais une sensibilité inattendue au ponatinib, en l’absence de mutation d’ABL1 susceptible d’expliquer ces réponses.Dans le but de caractériser la protéine RCSD1-ABL1, de comprendre ces profils de réponse aux ITK et de rechercher un traitement optimal de ces leucémies, nous avons cloné le produit de fusion à partir des blastes leucémiques de la patiente. Les constructions obtenues ont été transfectées dans le modèle cellulaire BaF3, ce qui nous a permis : 1) de démontrer et 2) de disséquer pour la première fois l’oncogénicité et la signalisation de la protéine de fusion, au moins partiellement distincte de celle de BCR-ABL1 et notamment concernant l’activation de la voie JAK/STAT; 3) de purifier RCSD1-ABL1 et de révéler l’impact inattendu du bras N-terminal RCSD1 sur l’activité catalytique de l’enzyme et sa sensibilité aux ITK ; 4) d’intégrer ces données et de démontrer l’effet potentialisateur d’inhibiteurs de la voie JAK/STAT sur l’activité des ITK dans les cellules transduites par RCSD1-ABL1 mais pas celles exprimant BCR-ABL1. Enfin, le profilage chémo-génomique de prélèvements issus de 3 patients nous a permis de conforter nos résultats, et de proposer des bases précliniques de traitements personnalisés ciblant ces mécanismesThe t(1;9)(q24;q34) translocation, generating the RCSD1-ABL1 fusion protein, is found in bad prognosis LAL cases. The oncogenic properties of RCSD1-ABL1 are unknown and the structure of the RCSD1 portion as well as its impact on RCSD1-ABL1 activity and signaling is yet to be determined. We recently reported the case of a patient with ALL associated with a RCSD1-ABL1 rearrangement that was resistant or poorly responsive to a large number of TKIs but was sensitive to Ponatinib, with no mutation that could explain this.In order to characterize this fusion protein, understand its response profile to TKI and optimize therapeutic approaches for these patients, we cloned the RCSD1-ABL1 gene from the patient sample and expressed it in the cellular model BaF3. This allowed us to 1) Demonstrate and 2) Study for the first time the oncogenic properties and signaling of the fusion protein, which is partially distinct from that of BCR-ABL1, especially regarding the JAK/STAT pathway; 3) Purify RCSD1-ABL1 and reveal the impact of the RCSD1 N-terminal portion on the enzyme activity and its TKI sensitivity; 4) Integrate this data and demonstrate the potentiating effect of JAT/STAT pathway inhibitors on TIK activity in cells expressing RCSD1-ABL1 but not in cells expressing BCR-ABL1.Finally, the chemo-genomic profiling of samples from three B-ALL t(1;9)(q24 ;q34) allowed us to consolidate our results and to propose preclinical bases for personalized treatments targeting the identified mechanisms
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Okada, Masayuki. "A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL positive human leukemic cells : caspase-independent, necrosis-like programmed cell death mediated by serine protease activity." Kyoto University, 2005. http://hdl.handle.net/2433/145297.
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Bewry, Nadine N. "STAT3 Contributes to Resistance Towards BCR-ABL Inhibitors in a Bone Marrow Microenvironment Model of Drug Resistance in Chronic Myeloid Leukemia Cells." [Tampa, Fla] : University of South Florida, 2009. http://purl.fcla.edu/usf/dc/et/SFE0002892.
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Nishihara, Toshio. "Effects of the Tyrosine Kinase Inhibitor, Imatinib Mesylate on a Bcr-Abl-Positive Cell Line : Suppression of Autonomous Cell Growth but No Effect on Decreased Adhesive Property and Morphological Changes." Kyoto University, 2004. http://hdl.handle.net/2433/147461.
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Heurteau, Foulon Stéphanie. "Prévalence, qualité de vie et coût de la Leucémie Myéloïde Chronique en France Using healthcare claims data to analyze the prevalence of BCR-ABL-positive chronic myeloid leukemia in France: A nationwide population-based study Health state utility and quality of life measures in patients with chronic myeloid leukemia in France." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS574.
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La leucémie myéloïde chronique (LMC) est une hémopathie maligne rare dont le pronostic a été transformé à partir des années 2000 par les inhibiteurs de tyrosine kinase (ITK). L’augmentation spectaculaire de l’espérance de vie des patients a conduit à une augmentation de la prévalence de la LMC. D’une maladie mortelle à moyen terme, la LMC est devenue une maladie chronique nécessitant la prise quotidienne d’ITK pendant plusieurs années. Les ITK sont des traitements onéreux qui, pris au long cours par un nombre croissant de patients, augmentent le fardeau économique de la maladie. Ces traitements ne sont pas dénués d’effets secondaires qui peuvent altérer la qualité de vie des patients. En France, il existe cependant peu de données sur la prévalence, la qualité de vie et les coûts induits par la maladie.Le Système National des Données de Santé (SNDS) est une base de données médico-administratives couvrant 98,8% de la population française et contenant les données exhaustives de consommation de soins remboursés par l’Assurance Maladie. Nous avons construit et validé un algorithme d’identification des patients ayant une LMC dans le SNDS à partir de leur consommation de soins et estimé la prévalence de la maladie au 31 décembre 2014. Sur la population de patients identifiés par l’algorithme, nous avons estimé le coût des ITK en 2013 et en 2014 en adoptant la perspective de l’Assurance Maladie. Nous avons complété ce travail par une enquête transversale réalisée en 2018 auprès de patients atteints de LMC pour recueillir leurs données de qualité de vie à l’aide d’un questionnaire générique (EuroQol EQ-5D-3L), d’un questionnaire spécifique au cancer (EORTC-QLQ-C30) complété par son module spécifique à la LMC (EORTC-QLQ-CML-24).L’algorithme a identifié 10 789 patients ayant une LMC en France au 31 décembre 2014, correspondant à une prévalence brute de la maladie de 16,3 pour 100 000 habitants [intervalle de confiance à 95% 16,0-16,6]. Pour la population prévalente de 10 158 patients atteints de LMC en 2013, le montant total des ITK remboursés par l’Assurance Maladie était de 238 millions d’euros, tous régimes confondus. Ce montant s’élevait à 247 millions d’euros pour les 10 789 patients prévalents en 2014. En 2014, l’imatinib représentait environ 55% de ce montant, suivi par le nilotinib (22%) et le dasatinib (22%). La qualité de vie des patients ayant une LMC est sensiblement altérée par rapport à celle de la population générale de même sexe et de même âge avec une altération de la fonction sociale, du niveau d’activité et de la fonction cognitive. La fatigue, la dyspnée et la douleur sont des symptômes marqués. La valeur moyenne d’utilité (écart-type) était de 0,72 (0,25) pour les patients en phase chronique et de 0,84 (0,21) pour les patients en rémission sans traitement.Au-delà des résultats épidémiologiques, cliniques et économiques, ce travail démontre la faisabilité, la pertinence mais aussi la complexité de l’utilisation d’une base de de données telle que le SNDS pour étudier des pathologies rares comme la LMCChronic myeloid leukemia (CML) is a rare myeloproliferative neoplasm whose prognosis has been transformed since the 2000s by tyrosine kinase inhibitors (TKI). The dramatic increase in patients' life expectancy has led to an increase in the prevalence of CML. CML has become a chronic disease that requires daily TKI treatment for several years, but which is compatible with a normal life span for the majority of patients. TKI are expensive treatments that, taken over the long term by an increasing number of patients, increase the economic burden of the disease. TKI have side effects that affect patients' quality of life. In France, however, there is little data on the prevalence of CML, on the economic burden and quality of life.The National Health Data System (Système National des Données de Santé, SNDS) is a health care claims database that covers 98,8% of the French population and contains exhaustive data on health cares reimbursed by the Health Insurance. We built and validated an algorithm identifying patients with CML in the SNDS, based on their healthcare consumption and estimated the prevalence of the disease on December 31st, 2014. On the population identified by the algorithm, we estimated the cost of TKI in 2013 and 2014 from a health insurance perspective. We also conducted a survey in CML patients to collect their quality of life data using generic (EuroQol EQ-5D-3L), cancer-specific (EORTC-QLQ-C30) and CML-specific (EORTC-QLQ-CML-24) questionnaires. Utility values in CML patients were assessed using the French EQ-5D-3L value set.The algorithm identified 10,789 patients with CML in France in 2014, corresponding to a crude prevalence of the disease of 16.3 per 100,000 inhabitants [95% confidence interval 16.0-16.6]. In the 10,158 prevalent CML patients in 2013, the reimbursement for TKI amounted to €238 million, all insurance schemes combined. This amount increased to €247 million for the 10,789 patients prevalent in 2014. In 2014, imatinib accounted for about 55% of TKI reimbursements, followed by nilotinib (22%) and dasatinib (22%). The quality of life in CML patients was significantly impaired compared to the general population of the same sex and age, mainly in the dimensions of social functioning, role functioning and cognitive functioning. Fatigue, dyspnea and pain were the symptoms with the highest deviation from general population norms. The mean utility score (standard deviation) was 0.72 (0.25) for patients in chronic phase and 0.84 (0.21) for patients in remission without treatment.Beyond the epidemiological, clinical and economic results, this work demonstrates that using a database such as the SNDS for research is feasible, relevant but also complex in rare diseases such as CML
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山本, 起代子, and Kiyoko Yamamoto. "Functionally deregulated AML1/RUNX1 cooperates with BCR-ABL to induce a blastic phase-like phenotype of chronic myelogenous leukemia in mice." Thesis, 2013. http://hdl.handle.net/2237/19156.
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Cheng, Hao-Yuan, and 鄭皓遠. "Combination of protein tyrosine kinase inhibitor AG1024 with paclitaxel enhances cell program death in BCR-ABL-mediated resistance of K562 cell line." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/30227831001776366712.
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碩士國立陽明大學
醫學生物技術研究所
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Chronic myelogenous leukaemia (CML) is a clonal malignancy of the pluripotent haematopoietic stem cell, characterised by an uncontrolled proliferation and expansion of myeloid progenitors expressing a fusion oncogene, BCR-ABL, the molecular counterpart of the Ph1 chromosome. Many evidences showed that the tyrosine kinase activity of BCR-ABL is able to activate several major signalling pathways in malignant cells, including Ras, JAK/STAT and PI3K/Akt and also prevent cells apoptosis under some antineoplastic agents such as paclitaxel. Targeting these abnormalities by blocking tyrosine kinase of BCR-ABL with STI571 provides a promising approach for the therapy of CML. The recent development of resistance to STI571 illustrates, however, that the use of other tyrosine kinase inhibitors could be of major interest for therapeutic purposes. To this end, the tyrosine kinase inhibitor Tyrphostin AG1024 was used to evaluate the effects on regulation of BCR-ABL expression, inhibition of cell proliferation and enhanced Taxol-induced apoptosis in BCR-ABL expressing cell lines, K562. As the result, Tyrphostin AG1024 was shown to downregulate the expression of BCR-ABL and anti-apoptosis factors such as Bcl-2 and Bcl-XL represented downstream of PI3K/Akt pathway in K562 cells. In addition, combination of Tyrphostin AG1024 with Taxol was able to inhibit cell proliferation, and enhance Taxol-induced apoptosis in 24 hours. Therefore, these evidences suggest that Tyrphostin AG1024 could be an enhancer of Taxol-based chemotherapy and provide another ways to fight CML.
Book chapters on the topic "BCR-ABL like"
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Baccarani, Michele, Fausto Castagnetti, Gabriele Gugliotta, Francesca Palandri, Simona Soverini, and Gianantonio Rosti. "Prognostic factors of chronic myeloid leukaemia." In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 63–78. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0005.
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Two decades following the successful introduction of the ABL tyrosine kinase inhibitors in clinics for the treatment of patients with chronic myeloid leukaemia (CML), the principal objective of treatment in chronic phase (CP) is survival, preferably without life-long therapy. In tandem, the methodology and tools for assessing the prognosis of the newly diagnosed patient with CML in CP has evolved substantially. Prior to the era of tyrosine kinase inhibitors (TKIs), risk assessment depended more on the response to treatment than on baseline characteristics. The Sokal score, introduced in 1984, was the first one dividing patients into three risk categories based on a mathematical formula taking into account the patient’s age, and baseline characteristics like blast cell count, spleen size, and platelet count. This, and the several other subsequent risk stratification methods developed during the chemotherapy and interferon-alpha era, have remained useful in the first-line TKI treatment, and identifies a variable proportion of high-risk patients with lower response rates and worse outcomes. In second line, the most important risk factors are the absence of haematologic or cytogenetic response on first line, the presence of hematologic toxicity the development of additional cytogenetic abnormities (ACA), and the development of BCR-ABL1 kinase domain mutations. In this chapter, we address the prognosis of CML and the various methods for risk stratification.
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Geyer, Holly L., Deepti Radia, Nicholas Sarlis, and Ruben A. Mesa. "Assessment of disease burden in patients with myeloproliferative neoplasms." In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 267–85. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0017.
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The BCR-ABL-negative myeloproliferative neoplasms (MPN) collectively represent a diverse assortment of clonal myeloid malignancies with variability in both genotypic and phenotypic presentation. MPN subtypes including essential thrombocythaemia (ET), polycythaemia vera (PV), myelofibrosis (MF), systemic mast cell disorders have been best studied in terms of symptom profiles and heterogeneously incur disease burdens that impact treatment options, overall quality of life, and survival. Recent treatment strategies have aimed to incorporate disease burden assessment into the selection of therapeutic interventions. Patient-reported outcome (PRO) tools have been developed to objectively assess the MPN disease burden in both clinical and trial formats. Their development supports recent FDA efforts to promote PROs in supporting labelling claims for novel targeted agents. This chapter discusses the spectrum of symptoms inherent to MPN disorders, available risk scoring tools and PRO options, and the emerging role of patient outcomes as trial endpoints.
Conference papers on the topic "BCR-ABL like"
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Tostes, Carine Pimenta Maurício Dantas, Kelly Costa De Almeida, Carolina V. A. Lutterbach De Carvalho, Gustavo Manso Fernandes, and Aislan Cristina R. F.Pascoal. "O EFEITO DA HIDROXIUREIA E MESILATO DE IMATINIBE NO TRATAMENTO DA LMC: RELATO DE CASO." In II Congresso Brasileiro de Hematologia Clínico-laboratorial On-line. Revista Multidisciplinar em Saúde, 2022. http://dx.doi.org/10.51161/hematoclil/14.
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INTRODUÇÃO: A leucemia mielóide crônica (LMC) é uma neoplasia mieloproliferativa relacionada à presença do gene de fusão BCR-ABL. É originada de uma célula-tronco hematopoiética anormal, que se caracteriza, como suas contrapartes normais. OBJETIVO: Avaliar o efeito do uso da hidroxiureia e mesilato de imatulibe nos parâmetros hematológicos em paciente diagnosticado com LMC. MATERIAL E MÉTODOS: Avaliação dos hemogramas realizados pelo paciente, após introdução das medicações. RESULTADOS: Paciente do sexo masculino, 57 anos, procurou auxílio médico após apresentar episódios recorrentes de cansaço, tontura, mal estar e dores abdominais. Dentre os diversos exames solicitados, em 23/08/21 os achados no hemograma apresentaram alterações consideráveis como leucometria de 40.820, com identificação de células jovens e trombocitose de 772.000/ mm³. Em relação à série vermelha foi evidenciada a presença de policromasia discreta, sendo encontrados 2 eritroblastos/100 células. O paciente foi encaminhado para hematologia oncológica, onde foi solicitado hemograma e Translocação BCR-ABL QUALITATIVO. Em 20/09/21 o resultado da translocação comprovou a presença de transcrito da fusão BCR-ABL. Perante o exposto, foi iniciado tratamento com hidroxiureia uma vez ao dia, esperava-se que a medicação fosse capaz de causar intercorrências no funcionamento da medula óssea, conseqüentemente a leucopenia em decorrência a mielodepressão. A dose administrada não foi capaz de causar melhoras no quadro. Por decisão médica o tratamento foi alterado para 2 comprimidos ao dia,com isso em 16/11/2021 o leucograma teve queda de 60%, no entanto a trombocitose se manteve, cumprindo o objetivo do uso da hidroxiureia no primeiro momento, que se limita a reduzir a contagem total de leucócitos. Embora tenha ocorrido a redução esperada, diante do quadro de leucocitose que se manteve, o paciente teve a dosagem da medicação aumentada para 4 comprimidos ao dia, como resultado, a leucometria atingiu a normalidade em 30/11/2021,com queda de aproximadamente 85% e plaquetas com redução de 42%. Iniciou-se uma segunda etapa do tratamento, utilizando o mesilato de imatinibe. A imatinibe causa inibição da proteína tirosinoquinase que inibe a atividade da Bcr-Abl. Em 30/12/21, o paciente apresentou taxa de leucometria e plaquetas dentro da normalidade. CONCLUSAO: Paciente apresentou resposta hematológica controlada, com possível remissão da LMC e aumento da sobrevida.
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Jesus, Anderson Avelino de, Samuel Santana Moura, Rebeca Santos Da Silva, Raqueline Pastor De Santana E. Santana, and Irlandia Oliveira Almeida. "LEUCEMIA MIELÓIDE CRÔNICA: O CROMOSSOMO PHILADELPHIA E O GENE BCR-ABL." In I Congresso Nacional Multidisciplinar de Oncologia On-line. Revista Multidisciplinar em Saúde, 2021. http://dx.doi.org/10.51161/rems/1529.
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Introdução: A Leucemia Mieloide Crônica (LMC) foi a primeira neoplasia humana relacionada a uma alteração cromossômica. Primeiros casos foram descritos em 1845. Porém, somente em 1960 quando Peter C. Nowell, estudando células de medula óssea de pacientes com LMC observou a presença de um pequeno cromossomo denominado Philadelphia (Ph) nestas células, sendo considerado um marco para a citogenética. Objetivo: Levantar relações da Leucemia Mieloide Crônica com o gene BCR-ABL e o cromossomo Philadelphia. Material e métodos: Trata-se de um estudo bibliográfico com abordagem descritiva e qualitativa, com uso de abordagens destinadas ao título e objetivo, mediante análise na plataforma PubMed. Periódicos incluídos é de 2010 a 2020 implementado o cenário atual. Resultados: A translocação recíproca entre cromossomos 9 e 22 é caracterizada como um distúrbio mieloproliferativo, distúrbio chamado de LMC que através desta translocação Philadelphia, mutação causadora da LMC. O gene da LMC produz uma proteína denominada de enzima BCR – ABL tirosina quinase, que permite enviar sinais para as células mieloides, sinalizando que acelere a divisão celular das células-tronco mielóide na medula óssea. Irá ocorrer o agrupamento destas células na medula óssea, eliminando os eritrócitos, plaquetas e leucócitos saudáveis. Nas células leucêmicas, em 90% dos pacientes é encontrado o cromossomo Philadelphia (Ph+) e uma pequena porcentagem não apresenta o cromossomo Philadelphia (Ph-) em suas células. Conclusão: O cromossomo chamado de filadélfia, vem sendo encontrado em células leucêmicas de pacientes com LMC, adiante o presente consiste em uma revisão de buscas, destinada ao mapeamento dos principais conceitos e limitações causadas por essa patologia que se dá pela alteração do gene BCR-ABL e do cromossomo Philadelfia pode vir a causar a LMC, ao conferir que a tirosina quinase pode desencadear um processo inibitório, estabelecer as condições necessárias para continuar as pesquisas de como os diferentes transcritos quiméricos intervêm na biologia das células.
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Bosso, Gabriela Jubilato, Letícia Cappellano, Luis Fernando Ventura Vilella, André Viu Matheus, and Ana Paula Pinto Batista. "LEUCEMIA MIELOIDE CRÔNICA EM ADOLESCENTE: RELATO DE CASO." In II Congresso Brasileiro de Hematologia Clínico-laboratorial On-line. Revista Multidisciplinar em Saúde, 2022. http://dx.doi.org/10.51161/hematoclil/28.
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Introdução: Rara em crianças e adolescentes, a leucemia mieloide crônica representa cerca de 2 a 3% dos casos de leucemia em menores de 15 anos. A doença mieloproliferativa é originada a partir da translocação dos cromossomos 9 e 22, dando origem ao cromossomo Philadelphia. O tratamento recomendado para crianças e adolescentes com LMC segue os protocolos de pacientes adultos pela falta de estudos na pediatria pela raridade da doença. O uso de inibidores de tirosina-quinase como o imatinibe tem mostrado bons resultados nos pacientes pediátricos. Objetivo: Relatar um caso de leucemia mieloide crônica em paciente pediátrico e o tratamento utilizado. Material e métodos: Os dados foram retirados do prontuário médico do paciente e foram coletados desde o momento da entrada do paciente no Grupo de Pesquisa e Assistência ao Câncer Infantil, por profissionais envolvidos durante toda a assistência através de anamnese, exame físico e exames laboratoriais. Resultado: Nesse estudo é relatado o caso de um paciente de 21 anos do sexo masculino que deu entrada no Grupo de Pesquisa e Assistência ao Câncer Infantil aos 14 anos com diagnóstico de LMC. Apresentou leucocitose, cromossomo Ph+ presente e fusão dos genes BCR/ABL1. Paciente está em tratamento com imatinibe desde 2014. A partir do diagnóstico de LMC no paciente pediátrico, a primeira linha de tratamento sugerida nos estudos mais recentes com adultos é o mesilato de imatinibe, que apresenta boa resposta e remissão da doença em um período de 12 a 18 meses. Para avaliação dos resultados do tratamento ou possibilidade de falha dele são observadas respostas hematológica, citogenética e molecular. O sucesso do tratamento em 18 meses é indicado pela ausência do cromossomo Ph+, resposta hematológica completa e razão BCR-ABL1/ABL menor ou igual a 0,1% na escala internacional. Conclusão: Pela escassez de casos e estudos da LMC na pediatria, o tratamento atual segue protocolos de pacientes adultos.
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Silva, Danielle Cardoso da, Miguel A. Moreira, Raquel C. Maia, and Flavia C. Vasconcelos. "Abstract A58: Bcr-Abl independent activation of Erk1/2 in an imatinib resistant cell line." In Abstracts: AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1557-3265.tcm17-a58.
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Lima, Luã De Morais De, and Cássia Bassetto Lorenzoni. "RECOMENDAÇÕES FARMACOLÓGICAS PARA TRATAMENTO DE LEUCEMIA MIELÓIDE CRÔNICA." In II Congresso Brasileiro de Hematologia Clínico-laboratorial On-line. Revista Multidisciplinar em Saúde, 2022. http://dx.doi.org/10.51161/hematoclil/51.
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Introdução: A Leucemia Mielóide Crônica (LMC) representa 14% das ocorrências de leucemia. Sua etiologia é relacionada a translocação 9:22 (cromossomo Filadélfia positivo). Assim, os tratamentos atuais para LMC vêm se mostrando promissores no incremento da sobrevida do paciente, a eles será dado foco neste resumo. Objetivos: Analisar as recomendações europeias para manejo da LMC e descrever os fármacos de primeira geração para tratamento da LMC. Material e métodos: O resumo sucedeu uma revisão da literatura mediante fontes qualitativas e ensaios clínicos. Nesse sentido, as bases de dados utilizadas para a pesquisa do material foram PebMed e Clinicalkey. Resultados: Enquanto monitoramento da LMC, doravante é recomendada a realização de hemograma quinzenal até a resposta hematológica ser atingida. PCR quantitativo para BCR-ABL é recomendado a cada três meses. Alvo terapêutico: 3 meses: ≤10%; 6 meses: ≤1%; 12 meses: ≤0,1%; Qualquer momento da evolução: ≤ 0,1%. Assim, o tratamento de primeira linha inclui os seguintes fármacos: Imatinibe: Dose padrão: 400mg 1x/dia. Em fase crônica o indivíduo é intolerante à dose padrão, em boa resposta reduz-se para 300mg/dia. Não possui contraindicação, todavia, pacientes portadores de insuficiência cardíaca e disfunção renal necessitam de acompanhamento. Desatinibe: Dose padrão: 100mg 1x/dia em fase crônica 70mg 2x/dia nas demais fases. Apresenta toxicidade pleuropulmonar. O principal efeito adverso é a ocorrência de derrame pleural, atenção a idosos e portadores de comorbidades. Nilotinibe: Dose padrão: 300mg 2x/dia na fase crônica 400mg 2x/dia nas demais fases. Os principais efeitos adversos graves são cardiovasculares e pancreatite. Conclusão: O tratamento é efetivo em grande parte dos casos, porém a particularidade do paciente deve sempre ser levada em conta.
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Vilella, Luis Fernando Ventura, Gabriela Jubilato Bosso, Leticia Cappellano, Natalia Marques Rodrigues, and André Viu Matheus. "LEUCEMIA MIELOIDE CRÔNICA (LMC) EM ADOLESCENTE DE 13 ANOS: RELATO DE CASO." In II Congresso Brasileiro de Hematologia Clínico-laboratorial On-line. Revista Multidisciplinar em Saúde, 2022. http://dx.doi.org/10.51161/hematoclil/29.
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Introdução:A Leucemia Mielóide Crônica (LMC) é uma patologia mieloproliferativa crônica e clonal; A doença é ocasionada pela translocação cromossomial, que ocorre entre os cromossomos 9 e 22 t(9;22) (q34;q11), originando uma nova configuração, denominada de Cromossomo Philadefia (Ph+), sendo este o desencadeante da inibição apoptótica, via Tirosino-Quinase. O protocolo de escolha para tratamento de LMC são justamente drogas que interferem no processo de proliferação celular das células hematopoiéticas, através da inibição da Tirosina-Quinase (iTK), e não drogas quimioterápicas que tem ação generalizada na divisão celular de diversas células. Objetivo: Relatar o caso de uma paciente jovem, de 13 anos, portadora de uma neoplasia hematológica pouco convencional para sua idade, Leucemia Mielóide Crônica. Materiais e Métodos: As informações expressas neste trabalho, na sessão de ‘Relato de Caso’ é oriunda da revisão de prontuário da paciente, onde é contido todo exame clínico, sendo esta considerado a anamnese e exame físico da paciente; assim como exames complementares, como: métodos diagnósticos, exames laboratoriais e exames de imagem. Resultados: Logo após que o paciente pediátrico é diagnosticado com LMC, é submetido a um protocolo com inicialmente 600mg/m³/dia, via oral, de Imatinibe- fármaco inibidor da Tirosina-Quinase. Esse tratamento é usado na LMC em adultos, sendo está a primeira escolha terapêutica. A boa evolução com tratamento é revelada pela queda da relação BCR-ACL1/ABL, quantificada através dos parâmetros da escala internacional; associado com uma melhora do quadro clínico-laboratorial, avaliando hemograma, funções renal e hepática. Conclusão: Não há evidências robustas o suficiente para estabelecer um protocolo padronizado para pacientes jovens que possuem LMC, o que implica diretamente na conduta médica mediante a esse paciente. Mesmo com uma incidência baixa, a LMC em jovens, é uma condição existente e que exige do profissional médico um suporte certo em combate à patologia. . É fundamental que haja novos estudos que pensem em um tratamento seguro para o paciente pediátrico, e que possa ser curativo e definitivo, com logística e resolutividade satisfatória.
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Soverini, Simona, Caterina De Benedittis, Alessandra Gnani, Ilaria Iacobucci, Fausto Castagnetti, Gabriele Gugliotta, Cristina Papayannidis, et al. "Abstract 1884: Resistance to second-line tyrosine kinase inhibitor treatment in imatinib-resistant Philadelphia-positive leukemia patients can be anticipated by ultra-deep sequencing of the BCR-ABL kinase domain using Roche 454 technology." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-1884.
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