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Ishida, Yoji, Kazunori Murai, Kohei Yamaguchi, Takuo Miyagishima, Motohiro Shindo, Kazuei Ogawa, Takahiro Nagashima, et al. "Pharmacokinetic (PK) and Pharmacodynamic (PD) Study Of Dasatinib In Chronic Phase Of Newly Diagnosed Chronic Myeloid Leukemia (CML-CP)." Blood 122, no. 21 (November 15, 2013): 4031. http://dx.doi.org/10.1182/blood.v122.21.4031.4031.
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Abstract Purpose Dasatinib is a novel kinase inhibitor of BCR-ABL and SRC family kinases. Dasatinib has shown promising anti-leukemic activity in chronic myeloid leukemi (CML). Tounderstand how to administer dasatinib with best efficacy and less adverse events, the pharmacokinetic (PK) properties of dasatinib and the relationship of PK and pharmacodynamic (PD) characteristics were investigated in newly diagnosed CML-chronic phase (CP) patients. Methods and Materials The PK analysis of dasatinib: The plasma concentrations of dasatinib (1, 2, 4 hr after taking dasatinib post 28 days) were determined by Francia's method using high performance liquid chromatography with mass spectrometry. PK analysis was performed using Phoenixâ NLMEâ1.2. The maximum plasma concentration (Cmax) was determined by visually inspecting the profiles of plasma drug levels. PD analysis of dasatinib: Phospho-CrkL in CD 34 positive cells was analyzed by flow cytometry using anti-phospho-CrkL (Tyr207) antibody after incubation of bone marrow mononuclear cells in the presence of dasatinib for 2 hours. PK/PD analysis: Area under the curve (AUC) and time above IC50 were calculated using Phonix WinNonlin 6.3. Results Twenty-eight newly diagnosed CML-CP patients were included. The correlation between the efficacy and PK/PD parameters were analyzed using Peason's correlation coefficient test (Table1). The efficacy(expression of bcr/abl at 1 month) was not correlated with AUC, Cmax, AUC/IC50 and Cmax/IC50 but significantly correlated with TAIC50 (r=0.4763, p=0.0104). The reduction rate at 1 month was correlated significantly with only TAIC50(r=0.5136, p=0.0052)(Figure 2). Eight cases reached MMR at 3 month among 15, whose TAIC50s were more than 12 hrs(53.3%), while only 2 cases reached MMR among 13, whose those were less than 12 hrs(15.4%). Conclusion Dasatinib has anti-leukemic activity in a time dependent manner. Exposure more than 12 hrs at TAIC50 will get benefits of better prognosis. Disclosures: No relevant conflicts of interest to declare.
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I, Jamal. "Plasma Cell Leukemia: An Overview." Haematology International Journal 5, no. 1 (2021): 1–2. http://dx.doi.org/10.23880/hij-16000175.
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Sumeet, Bajaj Preeti, Kasture Jyoti Uttamrao, and Shah Balbir Singh. "Plasma Cell Leukemia: Clinicopathological Profile of Five Cases." Indian Journal of Forensic Medicine and Pathology 9, no. 3 (2016): 189–91. http://dx.doi.org/10.21088/ijfmp.0974.3383.9316.18.
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Hudák, Renáta, Ildikó Beke Debreceni, Ivett Deák, Gabriella Gál Szabó, Zsuzsanna Hevessy, Péter Antal-Szalmás, Bjarne Osterud, and János Kappelmayer. "Laboratory characterization of leukemic cell procoagulants." Clinical Chemistry and Laboratory Medicine (CCLM) 55, no. 8 (July 26, 2017): 1215–23. http://dx.doi.org/10.1515/cclm-2017-0021.
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Abstract Background: In acute myeloid leukemias, there is an increased chance to develop thrombotic disorders. We hypothesized that in addition to leukemic promyelocytes, monocytic leukemia cells may also have a higher procoagulant activity. Methods: Fibrin formation was assessed by a one-stage clotting assay using a magnetic coagulometer. The thrombin generation test (TGT) of magnetically isolated normal human monocytes, intact leukemic cells and their isolated microparticles was performed by a fluorimetric assay. Phosphatidylserine (PS) expression of leukemic cells and microparticle number determinations were carried out by flow cytometry. Results: All cell lines displayed a significant procoagulant potential compared to isolated normal human monocytes. In the TGT test, the mean of lagtime and the time to peak parameters were significantly shorter in leukemic cells (3.9–4.7 and 9.9–10.3 min) compared to monocytes (14.9 and 26.5 min). The mean of peak thrombin in various monocytic leukemia cell lines was 112.1–132.9 nM vs. 75.1 nM in monocytes; however, no significant difference was observed in the ETP parameter. Factor VII-deficient plasma abolished all procoagulant activity, whereas factor XII-deficient plasma did not affect the speed of fibrin formation and thrombin generation but modulated the amount of thrombin. Factor XI-deficient plasma affected the time to peak values in one leukemic cell line and also attenuated peak thrombin. Leukemia cell-derived microparticles from all three cell lines exerted a procoagulant effect by significantly shortening the lagtime in TGT; there was a nonsignificant difference in case of ETP parameter. Conclusions: All investigated monocytic leukemia cell lines exhibited significant thrombin generation. This phenomenon was achieved by the procoagulants on the surface of leukemic cells as well as by their microparticles.
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S, Nibhoria. "Plasma Cell Leukemia–A Case Report and Review of Literature." Cytology & Histology International Journal 5, no. 1 (2021): 1–4. http://dx.doi.org/10.23880/chij-16000133.
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Plasma cell leukaemia (PCL) is one of the most aggressive and rarest forms of plasma cell dyscrasia. As prognosis is very poor, it is very important to recognize this entity sufficiently early so that one can offer combination chemotherapy at the earliest which can prolong survival.
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Keita, Mohamed, Sokhna Aissatou Touré, Elimane Seydi Bousso, Alioune Badara Diallo, Nata Dieng, Serigne Mourtalla Gueye, Blaise Felix Faye, Moussa Seck, and Saliou Diop. "PLASMA CELL LEUKEMIA: AN AGGRESSIVE DISEASE, A CAUSE OF DIAGNOSTIC ERROR." International Journal of Medical Science and Dental Health 10, no. 04 (April 7, 2024): 15–20. http://dx.doi.org/10.55640/ijmsdh-10-04-23.
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Plasma cell leukemia (LP) is a rare and aggressive plasma cell tumor that manifests as significant clonal expansion of plasma cells in the bone marrow and peripheral blood. It is considered primary when it presents at initial diagnosis and secondary when it occurs in patients with pre-existing multiple myeloma (MM). Because of the high frequency of extramedullary injuries, plasma cell leukemia is a major source of diagnostic error that can lead to fatality. We report a case of plasma cell leukemia diagnosed at the clinical haematology department of the CNTS in Dakar (Senegal).
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Heumann, D., G. Losa, C. Barras, A. Morell, and V. von Fliedner. "Characterization of acute undifferentiated leukemia by combined analysis of plasma membrane-associated gamma-glutamyltranspeptidase and soluble terminal transferase." Blood 66, no. 2 (August 1, 1985): 255–58. http://dx.doi.org/10.1182/blood.v66.2.255.bloodjournal662255.
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gamma-Glutamyltranspeptidase (gamma-GT) is a plasma membrane-associated enzyme present in blasts of certain acute leukemias. We analyzed 90 cases of undifferentiated and differentiated acute leukemias for gamma- GT, using a colorimetric assay. Blasts of all patients with common acute lymphoblastic leukemia (ALL) and T-ALL were negative for gamma-GT (less than 5 units). In contrast, gamma-GT was significantly elevated in acute myeloblastic or monoblastic leukemia blasts (P less than .001). In 16 cases of acute undifferentiated leukemia (AUL) studied, the levels of gamma-GT ranged from 0 to 93 units; in eight cases, gamma- GT was positive (greater than 5 units), and six of these had 2% to 5% Sudan black-positive leukemic cells in the blast-enriched suspension. Combined gamma-GT/TdT analysis revealed that both enzyme markers were mutually exclusive in 75% of AUL cases, suggesting that gamma-GT+/TdT- blasts are of nonlymphoid origin, and gamma-GT-/TdT+ blasts are of lymphoid origin. Two cases were devoid of both enzyme activities and could represent truly undifferentiated leukemia. Thus, combined gamma- GT/TdT analysis underlines the heterogeneity of AUL and appears to be useful in defining the lineage commitment of undifferentiated leukemic blasts.
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Zhang, Ke, Hagop M. Kantarjian, Wanlong Ma, XI Zhang, Xiuqiang Wang, Zeev Estrov, Chen-Hsiung Yeh, et al. "Use of Ubiquitin-Proteasome System Profiling for Differentiating Between Various Leukemic Processes." Blood 114, no. 22 (November 20, 2009): 4712. http://dx.doi.org/10.1182/blood.v114.22.4712.4712.
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Abstract Abstract 4712 The ubiquitin-proteasome system (UPS) plays a major role in cell homeostasis in normal and neoplastic states. Expression and function of the UPS system vary with the specific characteristics of individual cell types, suggesting that determination of UPS “signatures” could be useful in identifying various cell populations. Since direct analysis of cancer cells is often problematic, even in hematologic diseases, we explored the potential of using UPS signatures in plasma to differentiate between various leukemias. We first analyzed plasma UPS profiles of patients with acute myeloid leukemia (AML; n=111), acute lymphoblastic leukemia (ALL; n=29), advanced myelodysplastic syndrome (MDS; n=20), chronic lymphocytic leukemia (CLL; n=118), or chronic myeloid leukemia (CML; n=128; 46 in accelerated/blast crisis [ACC/BL], 82 in chronic phase), and 85 healthy control subjects. Plasma levels of proteasome, ubiquitin (poly-ubiquitin), and the 3 proteasome enzymatic activities (chymotrypsin-like [Ch-L], caspase-like [Cas-L], trypsin-like [Tr-L]) were measured. Specific activities were calculated by normalizing each of the 3 enzyme activities to the levels of proteasome protein in plasma (Ch-L/p, Cas-L/p, and Tr-L/p). These 8 variables were used in multivariate logistic regression models to differentiate between leukemic processes. UPS signatures provided clear differentiation between patients with a leukemic process and normal controls (AUC=0.991), using 6 different variables (Tr-L/P, Ch-L, Ch-L/p, Cas-L, Cas-L/P, ubiquitin). Distinguishing between acute (AML, ALL, MDS) and chronic (CML, CLL) processes was less efficient (AUC=0.853 using Tr-L, Tr-L/P, Cas-L/P, Ch-L/P, proteasome, Ch-L), likely due to the high proportion (36%) of CML patients in ACC/BL phase. However, UPS signatures generally yielded powerful differentiation between individual leukemias (Table). MDS was not well differentiated from AML (AUC=0.791), reflecting the significant biological overlap of these diseases. These data support the potential usefulness of the UPS profile to aid in the differential diagnosis of various leukemias. Disclosures: No relevant conflicts of interest to declare.
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Heumann, D., G. Losa, C. Barras, A. Morell, and V. von Fliedner. "Characterization of acute undifferentiated leukemia by combined analysis of plasma membrane-associated gamma-glutamyltranspeptidase and soluble terminal transferase." Blood 66, no. 2 (August 1, 1985): 255–58. http://dx.doi.org/10.1182/blood.v66.2.255.255.
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Abstract gamma-Glutamyltranspeptidase (gamma-GT) is a plasma membrane-associated enzyme present in blasts of certain acute leukemias. We analyzed 90 cases of undifferentiated and differentiated acute leukemias for gamma- GT, using a colorimetric assay. Blasts of all patients with common acute lymphoblastic leukemia (ALL) and T-ALL were negative for gamma-GT (less than 5 units). In contrast, gamma-GT was significantly elevated in acute myeloblastic or monoblastic leukemia blasts (P less than .001). In 16 cases of acute undifferentiated leukemia (AUL) studied, the levels of gamma-GT ranged from 0 to 93 units; in eight cases, gamma- GT was positive (greater than 5 units), and six of these had 2% to 5% Sudan black-positive leukemic cells in the blast-enriched suspension. Combined gamma-GT/TdT analysis revealed that both enzyme markers were mutually exclusive in 75% of AUL cases, suggesting that gamma-GT+/TdT- blasts are of nonlymphoid origin, and gamma-GT-/TdT+ blasts are of lymphoid origin. Two cases were devoid of both enzyme activities and could represent truly undifferentiated leukemia. Thus, combined gamma- GT/TdT analysis underlines the heterogeneity of AUL and appears to be useful in defining the lineage commitment of undifferentiated leukemic blasts.
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SOEBORG-OHLSEN, A., and OLE P. NIELSEN. "Case of Leukemic Myelomatosis (Plasma Cell Leukemia)." Acta Medica Scandinavica 122, no. 3 (April 24, 2009): 271–79. http://dx.doi.org/10.1111/j.0954-6820.1945.tb04503.x.
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Alitalo, Riitta, Ross Stephens, Antti Vaheri, and Satu Mustjoki. "Blast Cell-surface and Plasma Soluble Urokinase Receptor in Acute Leukemia Patients: Relationship to Classification and Response to Therapy." Thrombosis and Haemostasis 81, no. 05 (1999): 705–10. http://dx.doi.org/10.1055/s-0037-1614558.
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SummaryPlasminogen activation in leukemia has been less well characterized than in other malignancies. However, the increased tendency to bleeding and tissue infiltration by leukemic cells are processes in which plasminogen activation may be involved. We have examined plasma and the peripheral blood mononuclear cell fraction from 80 patients including 53 patients with newly diagnosed acute leukemia and 27 patients with other hematological disorders as well as 21 healthy controls. In 28 of 29 examined patients with acute myeloid leukemia (AML) and in two of three patients with hybrid leukemia we found urokinase receptor (uPAR) on the cell surface, while most (7/9) samples from patients with acute lymphoblastic leukemia (ALL) were negative for uPAR. The plasma mean value for soluble uPAR (suPAR) was significantly elevated in patients with AML and ALL. In AML the highest values were found in patients who had residual disease after several cycles of chemotherapy. Compared to controls the uPA antigen levels in patient plasmas were elevated and decreased along with uPAR during treatment. Our results suggest that cell surface uPAR may be a useful marker for leukemia classification and in our material a high level of plasma suPAR correlated with resistance to chemotherapy in AML.
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Aljurf, Mahmoud, Hala Abalkhail, Amal Alseraihy, Mouhab Ayas, Abdullah Al-Jefri, Ali Al-Ahmari, Asim F. Belgaumi, et al. "Chimerism Analysis of Free Circulating DNA in the Prediction of Relapse in Patients with Acute Leukemia Treated with Stem Cell Transplantation,." Blood 118, no. 21 (November 18, 2011): 3533. http://dx.doi.org/10.1182/blood.v118.21.3533.3533.
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Abstract Abstract 3533 Background: Predicting relapse after hematopoietic stem cell transplantation (HSCT) in hematologic malignancies remains a challenge, especially when there is no specific molecular marker for the leukemic cells. Early detection of relapse and intervention prior to florid relapse will, in general, improve outcome. Donor chimerism has been extensively explored in predicting relapse, but specificity and sensitivity of this approach remain low. Currently, post-transplant chimerism evaluation is performed on all circulating cells or on subpopulation of the circulating cells. However, decrease in donor DNA (cells) can be caused by factors other than relapsing leukemic cells. Free circulating DNA in plasma has been used for diagnosis and prediction of cancer and for early detection of relapse. Leukemic cells have high turnover pouring their DNA into circulation at a higher rate than normal cells. Because of this higher rate of turnover, plasma is enriched by leukemia-specific DNA. We hypothesized that plasma chimerism analysis may detect leukemia relapse earlier than cell chimerism. We studied DNA chimerism in the plasma from patients with hematologic malignancies and compared the pattern with that of cell chimerism. Most of our patients had acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) and were all treated with allogeneic hematopoietic stem cell transplantation (HSCT). Methods: CD3+ cells were separated from the myeloid cells using beads. Chimerism analysis was performed on both populations to determine the relative ratio of donor DNA. In addition, DNA was extracted from the plasma from the same samples and chimerism evaluation was carried out in the same fashion as cells. Results: We first analyzed samples from patients who had aplastic anemia but treated with allogeneic HSCT (N=11). These samples demonstrated that the plasma DNA chimerism is comparable to that seen in the granulocytes and significantly different from the chimerism in the lymphocytes. Since these patients are physiologically normal, this suggests that the majority of the circulating plasma DNA is generated by the turnover of granulocytes. Then we analyzed patients transplanted as a treatment for leukemia (N=84) and had 100% donor DNA in their granulocytes. Of these, 16 (19%) patients had clinical evidence of relapse. All patients with relapse had >10% recipient DNA in the plasma reflecting the relapsing leukemic cells. One of these patients had a relapse only in testes without bone marrow involvement and his plasma chimerism was positive for recipient DNA while both lymphocytes and granulocytes showed 100% donor DNA. Only three of the 16 patients (19%) had more recipient DNA in the lymphocytes chimerism analysis. However, of the 84 samples, 16 samples (19%) showed more recipient DNA (>10%) in plasma than in granulocytes without evidence of relapse, but almost all these patients had neutropenia or thrombocytopenia. These patients are being followed up to determine if they will develop leukemia. Eight additional patients with mixed chimerism in granulocytes and lymphocytes were studied for DNA chimerism in plasma. Three of these patients had more recipient DNA in plasma than in granulocytes and the three patients had evidence of relapse, while the rest of the patients had no significant relative increase in recipient DNA (>10%) in plasma and had no evidence of relapse. Conclusion: Chimerism studies of plasma DNA might be useful in predicting early relapse after HSCT in patients with acute leukemia. Although further studies are needed, our data suggests that any increase above 10% in percentage of recipient DNA in plasma as compared to that in granulocytes should alert to potential relapse. This approach in predicting early relapse has significant advantage because it can be applied to all leukemias and does not require a leukemia specific marker. Disclosures: No relevant conflicts of interest to declare.
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Jain, Mili, Ashutosh Kumar, Uma Shankar Singh, Rashmi Kushwaha, Abhishek Kumar Singh, Madhu Dikshit, and Anil Kumar Tripathi. "Cellular and plasma nitrite levels in myeloid leukemia: a pathogenetic decrease." Biological Chemistry 398, no. 11 (October 26, 2017): 1259–65. http://dx.doi.org/10.1515/hsz-2017-0143.
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AbstractNitric oxide (NO) has a contributory role in hemopoietic cell growth and differentiation. The effects of NO on leukemic cell growth have been predominantly studied inin vitrosettings. This study was done to assess the alterations in nitrite level in myeloid leukemias. Thirty-six newly diagnosed cases of myeloid leukemia (16 AML and 20 CML) were enrolled in the study. Neutrophil precursors from the marrow aspirate and peripheral blood were separated into cell bands using the Percoll density gradient method of Borregard and Cowland. The blood plasma and marrow fluid was also collected. Nitrite (stable non-volatile end product of NO) was estimated in the cell bands, blood plasma and marrow fluid using Griess reagent. The mean nitrite level in all cell bands from peripheral blood, bone marrow, blood plasma, and marrow fluid of cases was significantly lower as compared to corresponding value in the controls. No significant difference between AML and CML was seen. On follow-up, analysis of 13 CML patients higher nitrite levels were seen (p>0.05). The significant decrease in nitrite levels in myeloid leukemia suggests a decrease in nitric oxide synthase (NOS) activity. Further work may unfold molecular targets for therapeutic role of NO modulators.
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Qian, Jun, Jiang Lin, Zi-xing Chen, Yong-jun Chen, Jiang-nong Cen, Yong-ning Zhang, Yong-hui Ji, and Zhen Qian. "Marrow Plasma Levels of Stromal Cell-Derived Factor-1α in Patients with Hematopoietic Malignancies Might Be Associated with the Migration of Leukemic Cells." Blood 106, no. 11 (November 16, 2005): 4559. http://dx.doi.org/10.1182/blood.v106.11.4559.4559.
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Abstract The chemokine, stromal cell-derived factor-1 (SDF-1), which is mostly produced by marrow stromal cells, has various effects on hematopoietic cell functions. Its crucial role in the survival, trafficking, and homing of hematopoietic stem cells and progenitor cells is currently established. Here we described the potential significance of bone marrow plasma levels of SDF-1α in patients with hematopoietic malignancies. The bone marrow plasma was obtained from 74 aspirate samples from 38 patients with acute myeloid leukemia (AML), 12 acute lymphoblastic leukemia (ALL) and 24 myelodysplastic syndrome (MDS). The concentration of SDF-1α was determined by a sandwich enzyme-linked immunosorbent assay (ELISA). The results revealed a significant negative correlation of marrow plasma levels of SDF-1 with peripheral white blood cells counts (r=−0.304, P<0.05). The patients with low or normal WBC count (<=10×109/L) had significantly higher SDF-1 levels than those with high WBC count (>10×109/L) (358.88±251.64 pg/mL vs 149.33±129.16 pg/mL, P<0.001). The correlation of SDF-1α levels with platelet counts was also observed (r=0.279, P=0.002). No statistically significant differences were observed in the marrow plasma levels of SDF-1α between normal and abnormal karyotypic groups. There was no significant difference between patients with AML and ALL (279.24±318.50 pg/mL vs 209.78±120.96 pg/mL, P>0.05), however, MDS patients had significantly higher SDF-1α levels (528.65±351.57 pg/mL) than AML and ALL patients (P<0.001). In the subtypes of AMLs, granulocytic leukemia has higher marrow plasma levels of SDF-1α (337.81±350.92 pg/mL, n=28) than mononuclear leukemia (104.94±96.12 pg/mL, n=7). Our results suggest that the migration of malignant leukemic hematopoietic cells, especially of mononuclear leukemic cells, might be associated with the marrow SDF-1α level.
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Wang, Yajie, Sha Hao, Ping Lu, Hui Cheng, Yuemin Gong, and Tao Cheng. "Leukemia Cell Infiltration Causes Defective Erythropoiesis Partially through MIP-1alpha." Blood 126, no. 23 (December 3, 2015): 1185. http://dx.doi.org/10.1182/blood.v126.23.1185.1185.
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Abstract Leukemia often results in severe anemia, which may significantly contributes to mortality and morbidity of the patients. However, the mechanisms underlying the insufficient erythropoiesis in leukemia have been poorly understood. In this study, with our recently established non-irradiated MLL-AF9 acute myeloid leukemia (AML) murine model (Cheng H et al, Blood 2015), we observed a significant decrease in hemoglobin and red blood cells (RBCs) of Peripheral blood (PB) in the leukemic mice (n=6 per group, p=0.0122 vs p=0.0003). The absolute numbers of the erythroblasts at different stages (Pro Es, Ery.A, Ery.B, Ery.C) in bone marrow (BM) were also reduced. Consistently, by gene set enrichment analysis (GSEA) of microarray data of LKS+ cells (GSE52506 ) from leukemic mice, we found significant down-regulation of erythroid differentiation related genes such as GATA1, FOG-1, LMO2 and KLF1. These genes were more significantly inhibited in megakaryocytic-erythroid progenitors (MEPs) and Pro Es from the leukemic mice. Notably, the MEPs were the most reduced subset among all the committed hematopoietic progenitor cells (HPCs) during leukemia progression (90% decrease compared to control, p = 0.0007). MEPs were gradually accumulated in the G0 phase (from 22% to 70%, p<0.001). In contrast, erythroblasts (Pro Es, Ery.A, Ery.B) were more cycling (G1/S/G2/M) in leukemic mice and the proportions of Annexin V+ cells in erythroblasts but not in MEPs were also increased during leukemia development. Colony-forming cell (CFC) assays revealed that BM plasma of leukemia mice exerted an inhibitory effect on both BFU-Es and CFU-Es of BM mononuclear cells (BMMNCs) but not on other types of colonies (40% decrease for CFU-Es, 60% decrease for BFU-Es, p<0.001). Consistently, BM plasma of AML patients could also reduce the yield of BFU-Es and CFU-Es from CD34+ cord blood cells (n=7, p=0.006). To determine which cytokines may be responsible for the inhibitory effect, we collected serum and BM plasma from control and leukemic mice for cytokine array analysis. Among the elevated cytokines, MIP-1alpha was previously reported to be up-regulated in leukemic stem cells and its higher expression was found in the majority of patients with leukemia and a subset of patients with lymphoma and myeloma according to the Oncomine data set. We also confirmed it in a cohort of untreated AML patients (n=32). Importantly, AML patients with higher expression of MIP-1alpha showed reduced survival time (median=13.08 months) compared with the patients with lower expression (median=25.86 months) based on the leukemia-gene-atlas (LGA) analysis (n=72). By the CFC assay and single cell culture with different subsets of hematopoietic stem cells (HSCs) and HPCs, MIP-1alpha was able to largely mimic the inhibitory effect on the erythroid differentiation at both stem cell and progenitor cell levels. Mechanistically, we observed higher expression of MIP-1alpha receptor CCR1 in HSCs, MEPs and erythroblasts than CCR5. Administration of CCR1 antagonist, BX471 could partially recover the yield of erythroid colonies after treatment of MIP-1alpha or leukemia BM plasma. An increase of phosphorylation of p38 (phos p38) and resulted down-regulation of GATA1 after MIP-1alpha treatment were documented by Western blots and immunostaining. In summary, our results demonstrate that leukemic cell infiltration causes severe inhibition of erythropoiesis largely at different erythroid precursor levels and this inhibitory effect is at least partially medicated by elevated MIP-1alpha level via CCR1-p38 activation in the leukemic microenvironment. Disclosures No relevant conflicts of interest to declare.
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Wada, H., M. Tomeoku, A. Deguchi, H. Suzuki, Y. Mori, M. Ito, K. Deguchi, and S. Shirakawa. "Anticoagulant Activity in Cell Homogenate of Adult T Cell Leukemia." Thrombosis and Haemostasis 59, no. 02 (1988): 197–201. http://dx.doi.org/10.1055/s-0038-1642753.
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SummaryThe hemostatic abnormality in 18 patients with adult T cell leukemia (ATL) was studied. Activated partial thromboplastin time (APTT) was slightly prolonged and prekallikrein activity was markedly low in these patients. The leukemic cell homogenate from these patients prolonged the recalcification time (RCT) of normal plasma; homogenates containing more than 3 ×103 cells/μi prolonged it, although a lower cell concentration shortened it. The crude anticoagulant fraction from the gel filtration, with a molecular weight of about 34,000, prolonged RCT. The crude anticoagulant did not affect prothrombin time (PT), thrombin activity or activated X activity at any concentration, but prolonged the contact activation test, inhibited the activation of prekallikrein and prolonged RCT of Fletcher trait, Fitzgerald trait and F XII deficient plasma. These effects of ATL cell homo-genate were stronger on platelet poor plasma than on platelet rich plasma. Although ATL cells had low procoagulant activity, increase of leukemic cells made anticoagulant activity predominant, might be the cause of hemostatic abnormality or amplify the bleeding tendency in patients with ATL.
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Gusella, Milena, Caterina Bolzonella, Rossella Paolini, Elisabetta Rodella, Laura Bertolaso, Cinzia Scipioni, Silvia Bellini, Antonio Cuneo, Felice Pasini, and Emilio Ramazzina. "Plasma matrix metalloprotease 9 correlates with blood lymphocytosis, leukemic cell invasiveness, and prognosis in B-cell chronic lymphocytic leukemia." Tumor Biology 39, no. 2 (February 2017): 101042831769432. http://dx.doi.org/10.1177/1010428317694325.
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The complex biology underlying chronic lymphocytic leukemia cell migration and tissue invasiveness is not yet completely understood and might provide novel predictive markers and therapeutic targets. A total of 36 patients out of treatment from at least 3 months were enrolled and followed up for a median period of 44.2 months (range: 4.4–99.2). Matrix metalloprotease 9 and tissue inhibitor of metalloproteases 1 plasma levels and production/release from lymphoid cells were measured by zymography and enzyme-linked immunosorbent assay (ELISA) analysis. Malignant and normal lymphocyte mobility and matrix-degradation capability were studied using a Boyden chamber system, with and without autologous plasma. Free matrix metalloprotease 9 plasma levels were related with blood lymphocytosis, especially in more advanced stages (p = 0.003), and higher concentrations were associated with an increased disease progression risk (hazard ratio = 9.0, 95% confidence interval = 1.5–13.8). Leukemic cells expressed and secreted very little matrix metalloprotease 9. On the contrary, normal lymphocytes derived from the same leukemic patients showed matrix metalloprotease 9 intracellular levels that were lower in subjects with higher blood lymphocytosis (p = 0.024) and more advanced stages (p = 0.03); the released quantities were inversely associated with matrix metalloprotease 9 plasma concentrations (p = 0.035). Leukemic cells had a reduced spontaneous mobility and matrix-degradation capability that were stimulated by autologous plasma (p = 0.001) and normal lymphocytes (p = 0.005), respectively. Matrix metalloprotease 9 affected cell invasiveness depending on concentration and disease stage. In conclusion, chronic lymphocytic leukemia cells have a reduced mobility, matrix-degradation capability, and matrix metalloprotease 9 production compared to their own autologous normal lymphocytes. They are exposed to matrix metalloprotease 9 of prevalently systemic origin whose higher levels are associated with both leukemic and normal lymphocyte accumulation in the peripheral blood and have a negative prognostic value.
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Cani, Alice, Carlotta Caterina Damanti, Federica Lovisa, Enrico Gaffo, Giulia Borile, Elisa Carraro, Pina Fusco, et al. "Plasma S-Evs Mirnas in Pediatric B Lineage Leukemia: Transforming Factors of Bone Marrow Niche." Blood 142, Supplement 1 (November 28, 2023): 4081. http://dx.doi.org/10.1182/blood-2023-188680.
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BACKGROUND Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and mature B-cell leukemia are characterized by dismal prognosis in case of relapse. Exosomes are crucial small extracellular vesicles (S-EVs) used by cells for intercellular communication, capable to modulate recipient cells through the release of small biological molecules (DNA, RNA, proteins). Tumor derived exosomes play an important role in leukemogenesis, disease progression, and organ invasion, due to their ability to induce molecular and functional changes within the bone marrow microenvironment (BME). Since little is known behind the mechanism used by leukemic cells to sustain tumor progression through exosomes release, this has become an exciting area to be investigated. OBJECTIVES This study aimed to provide novel insight about S-EVs-mediated small-RNA (sRNA) transfer within tumor niche and clarify how the crosstalk between tumor cells and cells from the microenvironment promote leukemia cells survival and progression. The characterization of leukemic S-EVs cargo led to the identification of new potential biomarkers of disease progression and treatments efficacy. DESIGN/METHODS RNA from plasma S-EVs samples of 17 mature B-cell leukemia, 16 BCP-ALL at diagnosis and 8 healthy donors (HD) were isolated and small-RNA sequencing on Illumina platform was performed; data were analyzed by miR&moRe2 pipeline. MiRNAs levels were quantified by qRT-PCR in an extended cohort including HDs and patients both at diagnosis and during treatment. Mesenchymal stroma cells (MSCs) derived from healthy BM were co-cultured with tumor cell lines by using transwell. MSCs were also directly treated with S-EVs isolated from mature B-cell leukemia and BCP-ALL cell lines. S-EVs exchange was detected by confocal microscopy. Cell viability, migration and adipocyte differentiation assays were then assessed. Finally, pharmacological treatment of tumor cells co-cultured or not with adipocytes was administered. RESULTS Analysis of the profile of sRNAs contained in plasma exosomes according to sRNA-sequencing showed a peculiar miRNA cargo in both BCP-ALL and mature B cell leukemia groups compared to HD, and revealed 15 and 40 sRNAs significantly deregulated, respectively. We prioritized and validated the upregulation of 6 miRNAs (3 in BCP-ALL and 3 in mature B-cell leukemia) in an enlarged cohort patients' S-EVs obtained at diagnosis and in reference cell lines. Of note, the expression of these miRNAs during follow-up significantly decreases, suggesting their tumor origin and corroborating their usefulness as tumor biomarkers. To sustain this hypothesis sRNA-seq data were integrated with gene expression profiles obtained from leukemia blasts, underlining the tumor origin of these miRNAs. The prediction analysis of the miRNAs-target genes highlighted the alteration of specific networks related to cell survival, migration and cell differentiation. Furthermore, we demonstrated the communication via exosome release between leukemic cells and the surrounding cells and how S-EVs play a crucial role in the modulation of BME components. In particular, treatment with tumor derived S-EVs increases MSCs migration ability and prompts their adipogenic differentiation. These results were also confirmed by prioritized miRNAs transfection in MSCs. Co-culture of leukemic cells with adipocytes demonstrated their ability to protect BCP-ALL and mature B-cell leukemia cell lines from chemotherapy: leukemia cells showed a decrease in cell proliferation and a reduction of apoptosis. In line, poor responders BCP-ALL patients showed at diagnosis a positive enrichment in their transcriptome of mechanisms related to adipogenesis and lipids beta-oxidations. CONCLUSIONS Our data demonstrated that leukemic cells and BM niche cells efficiently communicate between each other through S-EVs release and uptake, inducing MSCs rewiring, with enhanced migratory and differentiative properties in vitro. We noted a strong enrichment of common pathways stroked by all the miRNA validated and related to lipid metabolism and sustenance of adipogenesis. Our study demonstrated that the bone marrow modulation is due to leukemic miRNAs shuttled by S-EVs in MSC cells and that the BME rewiring prompt leukemia chemoresistance.
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Spertini, O., P. Callegari, AS Cordey, J. Hauert, J. Joggi, V. von Fliedner, and M. Schapira. "High levels of the shed form of L-selectin are present in patients with acute leukemia and inhibit blast cell adhesion to activated endothelium." Blood 84, no. 4 (August 15, 1994): 1249–56. http://dx.doi.org/10.1182/blood.v84.4.1249.1249.
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Abstract L-selectin is expressed by most leukocytes and mediates the initial step of adhesion to vascular endothelium. A feature of this adhesion receptor is to be shed from the cell surface. We report here the presence of high levels of the shed form of L-selectin (sL-selectin) in plasma from patients with acute leukemia. We also show that sL-selectin purified from acute leukemia plasma exhibits functional activity. The mean (+/- 1 SD) plasma level of sL-selectin among 100 healthy individuals was 2.1 +/- 0.7 micrograms/mL. This value was increased (> 2 SD above the mean) in 63% of 58 patients with acute lymphoblastic leukemia (ALL) and 59% of 93 patients with acute myelogenous leukemia ([AML] P < .001). Repeated measurements in 24 patients showed normal- range levels in 16 of 16 patients in complete remission and high levels in eight of eight patients with therapy-resistant acute leukemia or leukemia relapse. Furthermore, elevated sL-selectin levels were detected in cerebrospinal fluid of three patients with ALL suffering from a relapse limited to the central nervous system. Epitope mapping with monoclonal antibodies demonstrated that L-selectin shedding from leukemic blasts was accompanied by conformational changes of its epidermal growth factor-like domain. A functional role for sL-selectin purified from leukemic plasma was supported by its ability to completely inhibit L-selectin-dependent adhesion of blast cells to tumor necrosis factor-alpha (TNF-alpha)-activated endothelium in vitro. These results suggest that sL-selectin may have an important role in the regulation of leukemic cell adhesion to endothelium. In addition, monitoring of the sL-selectin level may be useful for evaluating leukemia activity, in particular for the detection of leukemia relapse.
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Spertini, O., P. Callegari, AS Cordey, J. Hauert, J. Joggi, V. von Fliedner, and M. Schapira. "High levels of the shed form of L-selectin are present in patients with acute leukemia and inhibit blast cell adhesion to activated endothelium." Blood 84, no. 4 (August 15, 1994): 1249–56. http://dx.doi.org/10.1182/blood.v84.4.1249.bloodjournal8441249.
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L-selectin is expressed by most leukocytes and mediates the initial step of adhesion to vascular endothelium. A feature of this adhesion receptor is to be shed from the cell surface. We report here the presence of high levels of the shed form of L-selectin (sL-selectin) in plasma from patients with acute leukemia. We also show that sL-selectin purified from acute leukemia plasma exhibits functional activity. The mean (+/- 1 SD) plasma level of sL-selectin among 100 healthy individuals was 2.1 +/- 0.7 micrograms/mL. This value was increased (> 2 SD above the mean) in 63% of 58 patients with acute lymphoblastic leukemia (ALL) and 59% of 93 patients with acute myelogenous leukemia ([AML] P < .001). Repeated measurements in 24 patients showed normal- range levels in 16 of 16 patients in complete remission and high levels in eight of eight patients with therapy-resistant acute leukemia or leukemia relapse. Furthermore, elevated sL-selectin levels were detected in cerebrospinal fluid of three patients with ALL suffering from a relapse limited to the central nervous system. Epitope mapping with monoclonal antibodies demonstrated that L-selectin shedding from leukemic blasts was accompanied by conformational changes of its epidermal growth factor-like domain. A functional role for sL-selectin purified from leukemic plasma was supported by its ability to completely inhibit L-selectin-dependent adhesion of blast cells to tumor necrosis factor-alpha (TNF-alpha)-activated endothelium in vitro. These results suggest that sL-selectin may have an important role in the regulation of leukemic cell adhesion to endothelium. In addition, monitoring of the sL-selectin level may be useful for evaluating leukemia activity, in particular for the detection of leukemia relapse.
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Singh, Tejinder, C. S. Premalata, K. V. Sajeevan, Ankit Jain, Ullas Batra, K. S. Saini, C. T. Satheesh, K. Govind Babu, and D. Lokanatha. "IgA Plasma Cell Leukemia." Journal of Laboratory Physicians 1, no. 01 (January 2009): 019–21. http://dx.doi.org/10.4103/0974-2727.44415.
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ABSTRACTPlasma cell leukemia (PCL) is a rare entity. There are two presentations of PCL, primary or secondary. The primary or de novo form of PCL presents with an acute and rapidly progressive leukemic phase. This form occurs when the patient has no pre-existing multiple myeloma (MM). The secondary form is the most advanced form of MM. The PCL is a rare disorder representing 1‒2% of the diagnosed cases of MM. Median age at presentation is usually above 50 years. The monoclonal protein in patients with PCL may be IgG (50%), IgA (15%), or in rare cases IgD or IgE (6%). We report a case of IgA primary PCL that is very rare. Patient was started on combination therapy with vincristine, adriamycin, and dexamethasone. There was poor response and patient died three months after diagnosis.
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Ismail, Ahmed, Katarzyna Anna Mierzejewska, Anna Janowska-Wieczorek, A. Robert Turner, Mariusz Z. Ratajczak, and Magdalena Kucia. "Novel Evidence That Pituitary Gonadotropins Directly Stimulate Human Leukemic cells—studies on Myeloid Cell Lines and Primary Patient AML and CML Cells." Blood 124, no. 21 (December 6, 2014): 2204. http://dx.doi.org/10.1182/blood.v124.21.2204.2204.
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Abstract Background . It has been postulated that hematopoietic stem/progenitor cells (HSPCs) can become specified from a population of migrating primordial germ cells (PGCs) isolated from embryos. In support of this intriguing possibility, HSPCs and PGCs are both highly migratory populations of stem cells, and evidence has accumulated for the sharing of several mutated genes (e.g., Sall4) as well as chromosomal aberrations between germline tumors and leukemias or lymphomas, which suggests their common clonal origin. In fact, we recently observed that normal murine HSPCs express several functional receptors for pituitary gonadal hormones, such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL), in addition to gonadal hormones including estrogens, androgen, and progesterone. Of note, the plasma levels of FSH and LH are elevated in older patients, which correlate with an increase in the incidence of myeloid leukemia. Hypothesis . Based on this, we have hypothesized that gonadotropic hormones play a yet underappreciated role in human malignant hematopoiesis. Materials and Methods . To address this issue, we performed a complex series of experiments employing human myeloid hematopoietic cell lines (KG-1a, K-562, U937, THP-1, HEL) and primary patient cells (AML, CML) to address the influence of pituitary sex hormones (FSH, LH, PRL) as well as gonadal sex hormones (androgen, estrogen, progesterone) on proliferation, migration, and adhesion of malignant cells. In addition, expression of the corresponding receptors was evaluated at the mRNA level by PCR, and their functionality was confirmed by signaling studies based on phosphorylation of major signal transduction pathways (AKT, MAPKp42/44, STAT). Results. We demonstrate for the first time that human myeloid leukemia cell lines express all pituitary gonadotropin and several gonadal hormone receptors and that FSH and LH receptors are functional on these cells, as evaluated by chemotaxis and adhesion assays. Moreover, FSH and LH receptors were expressed and functional on patient leukemic blasts in bone marrow (BM) and peripheral blood (PB). Human leukemic cells from cell lines and primary patient-derived cells also expressed some other gonadal hormone receptors (PRL-R, estrogen, progesterone, and androgen receptors), albeit at lower levels. Moreover, we observed that several human myeloid cell lines as well as primary patient leukemic cells responded to sex hormones by proliferation. Conclusions . Our data are the first to indicate that pituitary-secreted gonadotropins stimulate migration, adhesion, and proliferation of leukemic cells. This latter effect seems to be direct, as the receptors for these hormones respond to stimulation by phosphorylation of intracellular pathways involved in cell proliferation. Established human myeloid leukemia cell lines and primary patient blasts also responded to stimulation by gonadal sex hormones. Finally, our studies provide further evidence supporting a developmental link between hematopoiesis and the germline. Disclosures No relevant conflicts of interest to declare.
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Panzer-Gruemayer, Renate, Gerd Krapf, Dominik Beck, Gerhard Fuka, Christian Bieglmayer, Georg Mann, and Andrea Inthal. "Role of Erythropoietin Receptor in t(12;21) Positive Acute Lymphoblastic Leukemia." Blood 110, no. 11 (November 16, 2007): 2792. http://dx.doi.org/10.1182/blood.v110.11.2792.2792.
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Abstract The chromosomal translocation t(12;21)(p13;q22) resulting in the TEL/AML1 (also known as ETV6/ RUNX1) fusion gene is the most frequent translocation in childhood B cell precursor (BCP) ALL. This type of ALL is characterized by a unique molecular signature, which includes the overexpression of the gene for the erythropoietin receptor (EpoR). So far, it is not known what causes the overexpression of the EpoR gene or whether it has any effect on the t(12;21) positive leukemia. We therefore aimed to evaluate potential mechanisms responsible for the upregulation of the EpoR in t(12;21) leukemias and to find out whether signalling via this receptor affects survival or proliferation of leukemic cells. In addition, we planned to explore signalling pathways linked to the respective effects and to elucidate relevant mechanisms that might be essential for cell survival. We first excluded the possibility that the EpoR expression is upregulated as a consequence of high Epo levels in the plasma that are induced by the patients’ low hemoglobin (Hb) levels. While Hb levels from patients with t(12;21)+ ALL were significantly lower compared to those with other subtypes of BCP ALL (median, 6,15g/dL and 7,9g/dL, respectively; p<0.001 Wilcoxon 2- sample test), which correlated with high Epo levels in the plasma, the extent of EpoR mRNA expression of leukemic cells was independent of the respective amount of Epo in the individual patient’s plasma. Next, the influence of Epo on t(12;21) + leukemic cell lines was evaluated and revealed a consistent time and dose dependent increase in proliferation (Epo concentrations 10, 50, 100U/ml for 72 hours) determined by 3H-Thymidine incorporation. This effect was abrogated upon addition of a blocking anti-EpoR antibody thereby confirming the specificity of EpoR signalling. Since Epo may have apoptosis-modulating potential in EpoR expressing malignant cells, we tested its influence on drug-induced apoptosis. For this purpose IC50 concentrations of drugs that are commonly used for the treatment of children with BCP ALL were used. A reduction of glucocorticoid (GC)-induced apoptosis by Epo was demonstrated in t(12;21)+ cell lines while no effect was seen in combination with other drugs or in t(12;21) negative cell lines. Preliminary data indicate that NF-kappa B as well as PI3K/Akt pathways are triggered by Epo, implying that they play a role in this rescue mechanism. Given that cell lines may have intrinsic changes, we are presently evaluating whether the observed results can also be reproduced in primary leukemic cells. In support of this assumption are results in a limited number of primary t(12;21)+ leukemias showing a superior survival (MTT assay) and reduced apoptosis rate to GC when cultured in the presence of Epo. These findings are in contrast to those in t(12;21) negative BCP ALLs. In conclusion, our data indicate that overexpression of EpoR in t(12;21) positive leukemias is not induced by low Hb, a feature that is generally observed in patients with this type of leukemia. Binding of Epo to its receptor in vitro leads to enhanced survival and negatively affects the sensitivity to GCs. Whether these findings have any implications on the treatment and care of patients with t(12;21)+ leukemia needs to be addressed in further studies. Financial support: OENB10720, FWF P17551-B14 and GENAU-CHILD Projekt GZ200.136/1 - VI/1/2005 to RPG.
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H. Ouasif, H. Yahyaoui, M. Aitameur, and M. Chakour. "Plasma cell leukemia: A rare case." World Journal of Advanced Research and Reviews 18, no. 1 (April 30, 2023): 289–93. http://dx.doi.org/10.30574/wjarr.2023.18.1.0429.
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Plasma cell leukaemia is an extremely rare haematological malignancy with a poor prognosis. It is defined by the presence in the circulating blood of a number of plasma cells greater than 2 giga/L or greater than 20% of the leukocytes. It presents in two forms: secondary plasma cell leukaemia complicating a known multiple myeloma, and primary plasma cell leukaemia, which is leukaemic in origin. We report the observation of a 52-year-old Moroccan patient who presented with bone pain and general deterioration 3 months before hospitalisation. The haemogram revealed normocytic normochromic anaemia at 8.1 g/dL and hyperleukocytosis. The blood smear showed the presence of 38% of plasma cells. The myelogram confirmed the diagnosis of APL by showing a rich marrow with 63% dystrophic plasma cells. In this case, we emphasise the importance of careful cytological examination of the blood smear.
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Ma, W., I. Jilani, M. Gorre, M. Keating, H. Chan, R. Tseng, H. Kantarjian, S. O’Brien, F. J. Giles, and M. Albitar. "Plasma Is a Reliable Source of mRNA for Testing IgVH Mutation Status in Patients with Chronic Lymphocytic Leukemia." Blood 106, no. 11 (November 16, 2005): 2949. http://dx.doi.org/10.1182/blood.v106.11.2949.2949.
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Abstract The mutational status of the immunoglobulin heavy-chain variable-region (IgVH) gene in the leukemic cells of patients with chronic lymphocytic leukemia (CLL) is an important prognostic marker. Lack of IgVH mutation is associated with rapid disease progression and shorter survival. The assay used to determine IgVH mutation status requires specific amplification of the mRNA of the expressed clonal IgVH gene in CLL. However, in some patients with CLL or lymphocytic lymphoma, the bulk of the disease resides in the lymph nodes or bone marrow, with few circulating leukemic cells. In addition, contamination of leukemic clonal cells by reactive polyclonal plasma cells can cause difficulty in obtaining homogenous IgVH mRNA for sequencing, and may therefore lead to failed sequencing or sequencing of the wrong IgVH mRNA. We have reported that plasma is enriched with leukemia-specific DNA, RNA, and protein because of the high turnover of leukemic cells relative to non-neoplastic cells. We thus reasoned that plasma might be a more reliable source of IgVH mRNA than cells from peripheral blood or bone marrow, where mixed populations of leukemic cells and non-neoplastic lymphocytes or plasma cells could hinder sequencing. We tested the plasma from 8 patients in whom routine (cell-based) testing for IgVH mutation status failed to yield results due to a paucity of leukemic cells (<10% of total cells). The plasma of all the 8 samples showed unique, easily defined amplification products of the IgVH mRNA. Sequencing of these products showed the presence of mutated IgVH in 5 patients and unmutated IgVH in 3. Testing paired plasma and cell samples from 19 patients with CLL showed identical mutation rates and family types of the expressed IgVH gene. In contrast, plasma from 20 normal individuals showed no IgVH amplification products that could be sequenced. This data suggest that plasma can be used as an alternative to cells for testing IgVH mutation status. More importantly, plasma is more reliable when few leukemic cells are in circulation and the bulk of the tumor is in the bone marrow or lymph nodes.
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Aguayo, Alvaro, Hagop Kantarjian, Taghi Manshouri, Cristi Gidel, Elihu Estey, Deborah Thomas, Charles Koller, et al. "Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes." Blood 96, no. 6 (September 15, 2000): 2240–45. http://dx.doi.org/10.1182/blood.v96.6.2240.
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Abstract Angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-α (TNF-α), tumor growth factor-α (TGF-α), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-α, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-α levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-α in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.
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Aguayo, Alvaro, Hagop Kantarjian, Taghi Manshouri, Cristi Gidel, Elihu Estey, Deborah Thomas, Charles Koller, et al. "Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes." Blood 96, no. 6 (September 15, 2000): 2240–45. http://dx.doi.org/10.1182/blood.v96.6.2240.h8002240_2240_2245.
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Angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-α (TNF-α), tumor growth factor-α (TGF-α), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-α, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-α levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-α in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.
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Kalász, Vera, Tihamér Pap, György Csanaky, and Gábor Kelényi. "Endothelial cell receptors on leukemic plasma cells." Leukemia Research 13, no. 9 (January 1989): 863–68. http://dx.doi.org/10.1016/0145-2126(89)90100-8.
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Gonzalez-Paz, Natalia C., Scott Van Wier, Rafael Santana-Davila, Gregory Ahmann, Tammy Price-Troska, Kimberly Henderson, Morie Gertz, Robert Kyle, Philip Greipp, and Rafael Fonseca. "Plasma Cells from Secondary Plasma Cell Leukemia Display Different Cytogenetics Pattern When Compared with Primary Plasma Cell Leukemia." Blood 106, no. 11 (November 16, 2005): 3267. http://dx.doi.org/10.1182/blood.v106.11.3267.3267.
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Abstract Background: Plasma cell leukemia (PCL) is a rare plasma cell (PC) dyscrasia which may be designated as primary (PPCL) or de novo PCL when recognized at the time of diagnosis and secondary (SPCL) when there is leukemic transformation of a previously recognized multiple myeloma (MM). PCL has been reported to exhibit distinct clinical and immunophenotypic features that distinguish it from MM, but little is known about the specific genetics of this disease. To better understand the genetic features of the clonal PC from PPCL and SCPL we assessed in these patients the molecular and cytogenetic abnormalities most commonly found in MM. Patients and Methods: In our study we analyzed 3 groups of patients; 18 with PPCL, 23 with SPCL and a control group of 345 newly diagnosed MM previously published. Diagnostic criteria for PCL followed the presence of >2 x103/L PC in PB (Kyle et al. Arch Intern Med1974; 133–813–8). Cytogenetic abnormalities were assessed by the c-Ig FISH method; mutational analysis was performed using Conformational-sensitive gel electrophoresis (CSGE). Methylation was analyzed by methyl specific PCR (MSP) after bisulfite genomic DNA modification. Results: Translocation of immunoglobulin heavy chain with Cyclin D1 (t (11; 14)) was present in 76.9% (10 of 13) of PPCL, 71% (5 of 7) of SPCL, in contrast to 15.8% (53 of 336) of MM cases. Translocations’ involving the FGFR3-MMSET genes (4p16.3 locus) and c-MAF (16q32) genes were not observed among 10 patients studied with PPCL, but were present in 12.7 % each in SPCL. The t (4;14)(p16;q32) was present in 12.7% cases of MM and the t(14;16)(q32;q23) was present in 4.6 % of MM cases. Deletion of 17p13.1 (p53 locus) was found in 10% (37 of 345) of MM cases, 53.8% (7 of 13) for PPCL and 42.8% (3 of 7) for SPCL. Deletion of 13q was present in 54.2% (176 of 325) of MM, 76.9 % (10 of 13) of PPCL and 57.1% of SPCL. Ras mutations were found in 15% (2/13) of PPCL, located in codon 1 and 2 of the K-ras gene. In addition, 23% for SPCL presented mutations in the N-ras gene. Two mutations were located in codon 2 of N-ras and 1 patients in showed a mutation in codon 1 of K-ras gene. Ras mutations were present in 27% of MM cases. Mutations for p53 gene were present in 30.7% (4/13) of PPCL, 17% (3/17) for SPCL and 5% for MM. Methylation specific PCR for p16 gene was found in 23% (3/13) of PPCL, 29% of SPCL and 33.9% (149/439) of MM. Hypermethylation of p14 was not detected in PPCL but a 23 % was found in SPCL. Conclusions: In this study we demonstrate that PCs from PPCL more frequently carry the t (11; 14). Comparing SPCL and MM, PC’s from de novo PPCL do not show t (4; 14) or (16; 14). Deletion of 13q was more prevalent among patients with PPCL. Ras mutations appear to be as frequent in MM as in PPCL and SPCL. Mutations in p53 appeared to be more prevalent in PPCL than in SPCL and MM. Hypermethylation of p16 does not differ while hypermethylation of p14 is more frequent in SPCL than PPCL. These characteristics may lead to a different onset or disease evolution of PPCL compared to MM and secondary plasma cell leukemia and this may be important for diagnostic and treatment.
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Yang, Jun, Xin Liu, Susan B. Nyland, Ranran Zhang, Lindsay K. Ryland, Kathleen Broeg, Kendall Thomas Baab, Nancy Ruth Jarbadan, Rosalyn Irby, and Thomas P. Loughran. "Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway." Blood 115, no. 1 (January 7, 2010): 51–60. http://dx.doi.org/10.1182/blood-2009-06-223719.
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Abstract Large granular lymphocyte (LGL) leukemia results from chronic expansion of cytotoxic T cells or natural killer (NK) cells. Apoptotic resistance resulting from constitutive activation of survival signaling pathways is a fundamental pathogenic mechanism. Recent network modeling analyses identified platelet-derived growth factor (PDGF) as a key master switch in controlling these survival pathways in T-cell LGL leukemia. Here we show that an autocrine PDGF regulatory loop mediates survival of leukemic LGLs of both T- and NK-cell origin. We found high levels of circulating PDGF-BB in platelet-poor plasma samples from LGL leukemia patients. Production of PDGF-BB by leukemic LGLs was demonstrated by immunocytochemical staining. Leukemic cells expressed much higher levels of PDGFR-β transcripts than purified normal CD8+ T cells or NK cells. We observed that phosphatidylinositol-3-kinase (PI3 kinase), Src family kinase (SFK), and downstream protein kinase B (PKB)/AKT pathways were constitutively activated in both T- and NK-LGL leukemia. Pharmacologic blockade of these pathways led to apoptosis of leukemic LGLs. Neutralizing antibody to PDGF-BB inhibited PKB/AKT phosphorylation induced by LGL leukemia sera. These results suggest that targeting of PDGF-BB, a pivotal regulator for the long-term survival of leukemic LGLs, may be an important therapeutic strategy.
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Gertz, M. A., and F. K. Buadi. "Plasma cell leukemia." Haematologica 95, no. 5 (May 1, 2010): 705–7. http://dx.doi.org/10.3324/haematol.2009.021618.
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Chauhan, Shaylika, Priya Jaisinghani, Jaivir Rathore, Hassan Tariq, Yesenia Galan, Arjun Madhavan, Haris Rana, and Douglas Frenia. "Plasma cell leukemia." Journal of Family Medicine and Primary Care 7, no. 2 (2018): 461. http://dx.doi.org/10.4103/jfmpc.jfmpc_310_17.
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Maslak, P. "Plasma Cell Leukemia." ASH Image Bank 2002, no. 0628 (June 28, 2002): 100375. http://dx.doi.org/10.1182/ashimagebank-2002-100375.
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Maslak, P. "Plasma Cell Leukemia." ASH Image Bank 2002, no. 0719 (July 19, 2002): 100390. http://dx.doi.org/10.1182/ashimagebank-2002-100390.
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Saito, T. "Plasma Cell Leukemia." ASH Image Bank 2004, no. 0414 (April 14, 2004): 101098. http://dx.doi.org/10.1182/ashimagebank-2004-101098.
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Kadin, M. "Plasma Cell Leukemia." ASH Image Bank 2004, no. 1120 (November 20, 2004): 101239. http://dx.doi.org/10.1182/ashimagebank-2004-101239.
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Maslak, P. "Plasma Cell Leukemia." ASH Image Bank 2005, no. 0712 (July 12, 2005): 101381. http://dx.doi.org/10.1182/ashimagebank-2005-101381.
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Maslak, P. "Plasma Cell Leukemia." ASH Image Bank 2005, no. 0829 (August 29, 2005): 101392. http://dx.doi.org/10.1182/ashimagebank-2005-101392.
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Fonseca, Rafael. "Plasma Cell Leukemia." Blood 114, no. 22 (November 20, 2009): SCI—4—SCI—4. http://dx.doi.org/10.1182/blood.v114.22.sci-4.sci-4.
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Abstract Abstract SCI-4 Introduction Plasma cell leukemia (PCL) represents an aggressive variant of multiple myeloma (MM) characterized by the presence of large number of circulating plasma cells (PC) in the peripheral blood. While some boundaries have been defined to establish a diagnosis of PCL (PC in the peripheral blood greater than 2×109/l-1 or 20% of leukocytes being plasma cells), these values are artificial, and most cases of PCL show extreme numbers of circulating plasma cells. PCL is part of a spectrum of the PC neoplasms where increasing numbers of circulating PC identify aggressive MM, yet many cases do not satisfy criteria for PCL. Historically PLC has been divided into “Primary PCL” (pPCL) when it represents the initial manifestation of a PC neoplasm, and “Secondary PCL”, or MM with leukemic transformation (MM-LT). Both entities share biologic and clinical similarities as aggressive variants of MM, but the latter represents a fulminant PC neoplasm with historic survival of only 1-2 months. In contrast, pPCL, while nevertheless aggressive, often will respond to induction treatment and can occasionally result in a durable response. Biology Because of the rarity of PCL (1% or less of all MM) the genetic description of the disease has been limited by lack of material for study. Nevertheless most PCL cases harbor IgH translocations (87% of pPCL and 82% in MM-LT). In particularly the t(11;14)(q13;q32) is common; observed in 35 to 70% of cases of pPCL. In contrast MM-LT contains most other genetic aberrations associated with MM pathogenesis, including the more benign genetic variants of the disease (e.g. hyperdiploid MM), and these cells are presumed to have acquired additional genetic features resulting in aggressive clonal proliferation and expansion. When karyotypes are informative (frequently in PCL) they are almost always non-hyperdiploid variant, mostly hypodiploid. Rare cases of hyperdiploid karyotypes have been observed in association with MM-LT. Monoallelic deletions of 17p13.1, at the TP53 locus and similar to those seen in MM, can be detected in 50% of pPCL and 75% of MM-LT. While mutations of TP53 area rare in MM they are common in PCL (24%), contributing to a substantial overall prevalence of TP53 inactivation of 56% in pPCL and 83% in MM-LT. Furthermore, we found the upstream tumor suppressor p14ARF, whose product directly binds MDM2 enhancing p53 function, to be inactivated by methylation in 29% of MM-LT. MYC abnormalities are only observed in 15% of cases and the distribution of chromosome 13 deletion/monosomy is similar to what would be expected for the corresponding karyotypic aberrations (85% in the hypodiploid pPCL and 50% in MM-LT). Treatment and future directions Historically the treatment of PCL has been unsatisfactory with few patients achieving durable remissions, and most dying within weeks to months after diagnosis. The impact of more intensive regimens (including autologous and allogeneic stem cell transplant) and of novel agents such as bortezomib and lenalidomide are not known. However, early data suggest, that the historic survival rates of pPCL (∼12 months) and MM-LT (∼1-2 months) will be improved by the aforementioned interventions. It is likely that with increasing survival of MM patients, MM-LT will become an increasingly common and difficult problem to manage. Disclosures Fonseca: Various: CME lectures; Halozyme: Consultancy; BMS: Consultancy; Medtronic: Consultancy; AMGEN: Consultancy. Off Label Use: Multiple agents to be used for the treatment of plasma cell leukemia. No agents are specifically approved for this indication although this is a variant of myeloma.
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Albarracin, Flavio, and Rafael Fonseca. "Plasma cell leukemia." Blood Reviews 25, no. 3 (May 2011): 107–12. http://dx.doi.org/10.1016/j.blre.2011.01.005.
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Hayman, Suzanne R., and Rafael Fonseca. "Plasma cell leukemia." Current Treatment Options in Oncology 2, no. 3 (June 2001): 205–16. http://dx.doi.org/10.1007/s11864-001-0034-4.
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Walker, B., and S. Elkins. "Plasma Cell Leukemia." Journal of Investigative Medicine 53, no. 1_part_4 (January 2005): 278. http://dx.doi.org/10.1177/1081558905053001639.
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Miljkovic-Licina, Marijana, Nicolas Arraud, Aicha Dorra Zahra, Patricia Ropraz, and Thomas Matthes. "Quantification and Phenotypic Characterization of Extracellular Vesicles from Patients with Acute Myeloid and B-Cell Lymphoblastic Leukemia." Cancers 14, no. 1 (December 23, 2021): 56. http://dx.doi.org/10.3390/cancers14010056.
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Extracellular vesicles (EVs) act in cell-to-cell communication, delivering cargo from donor to recipient cells and modulating their physiological condition. EVs secreted by leukemic blasts in patients with leukemia have been shown to influence the fate of recipient cells in the bone marrow microenvironment. Methods to quantify and to characterize them phenotypically are therefore urgently needed to study their functional role in leukemia development and to evaluate their potential as targets for therapy. We have used cryo-electron microscopy to study morphology and size of leukemic EVs, and nanoparticle tracking analysis and fluorescence triggering flow cytometry to quantify EVs in platelet-free plasma from a small cohort of leukemia patients and healthy blood donors. Additional studies with a capture bead-based assay allowed us to establish phenotypic signatures of leukemic EVs from 17 AML and 3 B-ALL patients by evaluating the expression of 37 surface antigens. In addition to tetraspanins and lineage-specific markers we found several adhesion molecules (CD29, and CD146) to be highly expressed by EVs from B-ALL and several leukemic stem cell antigens (CD44, CD105, CD133, and SSEA-4) to be expressed by EVs from AML patients. Further improvements in analytical methods to study EVs are needed before potentially using them as biomarkers for leukemia prognosis and follow-up.
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Badial, Peres R., Rebecca L. Tallmadge, Steven Miller, Tracy Stokol, Kristy Richards, Alexandre S. Borges, and M. Julia B. Felippe. "Applied Protein and Molecular Techniques for Characterization of B Cell Neoplasms in Horses." Clinical and Vaccine Immunology 22, no. 11 (August 26, 2015): 1133–45. http://dx.doi.org/10.1128/cvi.00374-15.
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ABSTRACTMature B cell neoplasms cover a spectrum of diseases involving lymphoid tissues (lymphoma) or blood (leukemia), with an overlap between these two presentations. Previous studies describing equine lymphoid neoplasias have not included analyses of clonality using molecular techniques. The objective of this study was to use molecular techniques to advance the classification of B cell lymphoproliferative diseases in five adult equine patients with a rare condition of monoclonal gammopathy, B cell leukemia, and concurrent lymphadenopathy (lymphoma/leukemia). The B cell neoplasms were phenotypically characterized by gene and cell surface molecule expression, secreted immunoglobulin (Ig) isotype concentrations, Ig heavy-chain variable (IGHV) region domain sequencing, and spectratyping. All five patients had hyperglobulinemia due to IgG1 or IgG4/7 monoclonal gammopathy. Peripheral blood leukocyte immunophenotyping revealed high proportions of IgG1- or IgG4/7-positive cells and relative T cell lymphopenia. Most leukemic cells lacked the surface B cell markers CD19 and CD21.IGHG1orIGHG4/7gene expression was consistent with surface protein expression, and secreted isotype and Ig spectratyping revealed one dominant monoclonal peak. The mRNA expression of the B cell-associated developmental genesEBF1,PAX5, andCD19was high compared to that of the plasma cell-associated markerCD38. Sequence analysis of the IGHV domain of leukemic cells revealed mutated Igs. In conclusion, the protein and molecular techniques used in this study identified neoplastic cells compatible with a developmental transition between B cell and plasma cell stages, and they can be used for the classification of equine B cell lymphoproliferative disease.
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Hanbali, Amr, Abdulaziz Alrajeh, and Walid Rasheed. "Plasma cell leukemia mimicking hairy cell leukemia." Hematology/Oncology and Stem Cell Therapy 8, no. 2 (June 2015): 91–92. http://dx.doi.org/10.1016/j.hemonc.2015.05.001.
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Yokota, Asumi, Shinya Kimura, Satohiro Masuda, Eishi Ashihara, Yoshimasa Urasaki, Yasuhito Terui, Martin Ruthardt, et al. "Anti-Tumor Effect of INNO-406, a Novel Bcr-Abl Inhibitor in Combination with Cyclosporin A Against the Murine Central Nervous System and Systemic Leukemia Model." Blood 110, no. 11 (November 16, 2007): 1598. http://dx.doi.org/10.1182/blood.v110.11.1598.1598.
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Abstract Central nervous system (CNS) is one of the major cites for extramedullary relapse of Ph+ leukemias, which have been treated with imatinib mesylate (IM). The reason for this is that IM is a substrate for P-glycoprotein (P-gp) at the blood brain barrier and effluxed by it. We have already shown in the last annual meeting that INNO-406 had much stronger anti-tumor effects against the murine CNS leukemia model compared with IM, and INNO-406 is also effluxed from the murine CNS by P-gp. In this study, we investigated the combination effect of INNO-406 and P-gp inhibitors, verapamil or cyclosporin-A (CsA). First, we examined the growth-suppressive effect of INNO-406 and the combination with the P-gp inhibitors against the BCR-ABL positive leukemic cell line, K562 and the P-gp-overexpressing K562, K562/D1-9 cell line. K562/D1-9 showed 10 times higher resistant to both IM and INNO-406 compared with K562. Furthermore, both verapamil and CsA synergistically augmented the effect of INNO-406. Next, we investigated the pharmacokinetics of INNO-406 when orally administrated with CsA to mice. Mice were administrated p.o. with 50mg/kg of CsA 2 hours before INNO-406. We found that the concentration of INNO-406 in the CNS elevated by 2 times when combined with CsA, while the plasma concentration was decreased to two thirds of that when singly administrated with INNO-406. It was suggested that the decreased plasma concentration of INNO-406 seen here resulted from the increased uptake into the CNS by CsA inhibiting P-gp at the blood brain barrier. These changes of the drug distribution to the murine tissues may alter the anti-leukemic effect of INNO-406, thus we planned to investigate the combination effect of INNO-406 and CsA in the murine models of both CNS and systemic leukemia. We found that CsA significantly augmented the anti-tumor effect of INNO-406 in the CNS leukemia model. Moreover, in spite of the decreased plasma concentration of INNO-406, the combination with CsA also prolonged the survival phase of the mice in the systemic leukemia model, more significantly than single treatment of INNO-406 (Figure). This may be explained by which CsA increased the intracellular uptake of INNO-406, resulted from the direct inhibition of drug efflux via P-gp expressed in the leukemic cells. Phase I clinical study on INNO-406 is now underway in MD Anderson Cancer Center and in Frankfurt University. From the results of this study, we expected the effective application of INNO-406 in combination with P-gp inhibitor to the patients suffering from refractory Ph+ leukemia as well as CNS relapse. Figure Figure
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Yuan, Yao, Siddha Kasar, Chingiz Underbayev, Sindhuri Prakash, and Elizabeth Raveche. "MicroRNAs in Acute Myeloid Leukemia and Other Blood Disorders." Leukemia Research and Treatment 2012 (June 17, 2012): 1–11. http://dx.doi.org/10.1155/2012/603830.
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Common blood disorders include hematopoietic cell malignancies or leukemias and plasma cell dyscrasia, all of which have associated microRNA abnormalities. In this paper, we discuss several leukemias including acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) and identify altered microRNAs and their targets. Immune disorders with altered blood levels of antibodies include autoimmune disorders, such as systemic lupus erythematosus (SLE) with associated anti-self-autoantibodies and immunoglobulin A nephropathy (IgAN) also have related microRNA abnormalities. The alterations in microRNAs may serve as therapeutic targets in these blood disorders.
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Sulistiandari, Sri, and Budiman . "SEL PLASMA LEUKEMIA HUBUNGAN DENGAN MIELOFIBROSIS." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 14, no. 3 (March 16, 2018): 123. http://dx.doi.org/10.24293/ijcpml.v14i3.937.
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Plasma cell leukemia (PCL) is a variant form of myeloma which contain more than >20% plasma cells and an absolute plasmacell content ≥ 2.000/mm3 in peripheral blood. PCL is a rare disorder, whole PCL with myelofibrosis is even more rare disorder. Thecorrelation between plasma cell leukemia and myelofibrosis is unclear. A 59-years-old woman referred to our hospital with generalweakness and severe anemia. Physical examination: looks pale, anaemic of conjunctiva, hepatosplenomegaly. The laboratory findingsare Hb 4.1 gr/dL, MCV 81 fL, MCH 26.7 pg, leucocytes 22.500/mm3, thrombocytes 26.000/mm3, reticulocytes 1.8%. The peripheralblood showed leucoerythroblastic morphology with teardrop cells and 32% plasma cells. Bone marrow aspiration revealed massiveplasma cell infiltrations (90%). Protein electrophoresis showed hypogammaglobulinemia. There is no evidence of osteolitic bone lesionon radiological examination. Clinical and laboratory finding above support the diagnosis of Primary Plasma Cell Leukaemia that maylead to myelofibrosis as a complication. Bone marrow biopsy is required to confirm diagnosis of myelofibrosis.
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Shimamura, R., J. Kudo, H. Kondo, K. Dohmen, H. Gondo, S. Okamura, H. Ishibashi, and Y. Niho. "Expression of the thymosin beta 4 gene during differentiation of hematopoietic cells." Blood 76, no. 5 (September 1, 1990): 977–84. http://dx.doi.org/10.1182/blood.v76.5.977.977.
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Abstract Thymosin beta 4 (T beta 4) was originally isolated as a thymic hormone. Its functional properties remain obscure; however, the N-terminal peptidic sequence could have a regulatory function on hematopoietic stem cell proliferation. To investigate the mechanism of T beta 4 expression, we studied T beta 4 gene expression in various leukemic cells and in established cell lines. Among leukemic cell samples obtained from leukemia patients, the T beta 4 gene was highly expressed in a lymphoid lineage, especially in adult T-cell leukemia (ATL) cells, rather than in a granulocyte lineage. The T beta 4 gene was more transcriptionally active in chronic B-cell leukemia than in acute B- cell leukemia, while it was inactive in plasma cell leukemia. We also found that cells from one of the ATL patients transcribed a heterogeneous message. T beta 4 messenger RNA increased in MOLT-3 during differentiation by 12-O-tetradecanoylphorbol-13-acetate (TPA), in HL60 cells induced by TPA or dimethylsulfoxide and K562 cells stimulated by cytosine arabinoside or hemin. The genomic sequence of T beta 4 is considered to be highly conserved. Only 1 of 20 genomes from normal or hematopoietic malignant cells showed restriction fragment length polymorphism. These findings, along with previous data, suggest that T beta 4 may be a new marker of differentiation of hematopoietic cells.
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Shimamura, R., J. Kudo, H. Kondo, K. Dohmen, H. Gondo, S. Okamura, H. Ishibashi, and Y. Niho. "Expression of the thymosin beta 4 gene during differentiation of hematopoietic cells." Blood 76, no. 5 (September 1, 1990): 977–84. http://dx.doi.org/10.1182/blood.v76.5.977.bloodjournal765977.
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Thymosin beta 4 (T beta 4) was originally isolated as a thymic hormone. Its functional properties remain obscure; however, the N-terminal peptidic sequence could have a regulatory function on hematopoietic stem cell proliferation. To investigate the mechanism of T beta 4 expression, we studied T beta 4 gene expression in various leukemic cells and in established cell lines. Among leukemic cell samples obtained from leukemia patients, the T beta 4 gene was highly expressed in a lymphoid lineage, especially in adult T-cell leukemia (ATL) cells, rather than in a granulocyte lineage. The T beta 4 gene was more transcriptionally active in chronic B-cell leukemia than in acute B- cell leukemia, while it was inactive in plasma cell leukemia. We also found that cells from one of the ATL patients transcribed a heterogeneous message. T beta 4 messenger RNA increased in MOLT-3 during differentiation by 12-O-tetradecanoylphorbol-13-acetate (TPA), in HL60 cells induced by TPA or dimethylsulfoxide and K562 cells stimulated by cytosine arabinoside or hemin. The genomic sequence of T beta 4 is considered to be highly conserved. Only 1 of 20 genomes from normal or hematopoietic malignant cells showed restriction fragment length polymorphism. These findings, along with previous data, suggest that T beta 4 may be a new marker of differentiation of hematopoietic cells.