scholarly journals Expression of the three myeloid cell-associated immunoglobulin G Fc receptors defined by murine monoclonal antibodies on normal bone marrow and acute leukemia cells

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1951-1956
Author(s):  
ED Ball ◽  
J McDermott ◽  
JD Griffin ◽  
FR Davey ◽  
R Davis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Monoclonal Antibodies ◽  
Acute Leukemia ◽  
Cell Sorting ◽  
Lymphoblastic Leukemia ◽  
Mononuclear Phagocytes ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Normal Bone Marrow ◽  
Normal Bone

Monoclonal antibodies (MoAbs) have been prepared recently that recognize the three cell-surface receptors for the Fc portion of immunoglobulin (Ig), termed Fc gamma RI (MoAb 32.2), Fc gamma R II (MoAb IV-3), and Fc gamma R III (MoAb 3G8) that are expressed on selected subsets of non-T lymphocyte peripheral blood leukocytes. In the blood, Fc gamma R I is expressed exclusively on monocytes and macrophages, Fc gamma R II on granulocytes, mononuclear phagocytes, platelets, and B cells, and Fc gamma R III on granulocytes and natural killer (NK) cells. We have examined the expression of these molecules on normal bone marrow (BM) cells and on leukemia cells from the blood and/or BM in order to determine their normal ontogeny as well as their distribution on leukemic cells. BM was obtained from six normal volunteers and from 170 patients with newly diagnosed acute leukemia. Normal BM cells were found to express Fc gamma R I, II, and III with the following percentages: 40%, 58%, and 56%, respectively. Cell sorting revealed that both Fc gamma R I and Fc gamma R II were detectable on all subclasses of myeloid precursors as early as myeloblasts. Cell sorting experiments revealed that 66% of the granulocyte-monocyte colony-forming cells (CFU-GM) and 50% of erythroid burst-forming units (BFU-E) were Fc gamma R II positive with only 20% and 28%, respectively, of CFU-GM and BFU-E were Fc gamma R I positive. Acute myeloid leukemia (AML) cells expressed the three receptors with the following frequency (n = 146): Fc gamma R I, 58%; Fc gamma R II, 67%; and Fc gamma R III, 26% of patients. Despite the fact that Fc gamma R I is only expressed on monocytes among blood cells, AML cells without monocytoid differentiation (French-American-British [FAB]M1, M2, M3, M6) were sometimes positive for this receptor. However, Fc gamma R I was highly correlated with FAB M4 and M5 morphology (P less than .001). Fc gamma R II was also correlated with FAB M4 and M5 morphology (P = .003). Cells from 11 patients with acute lymphoblastic leukemia were negative for Fc gamma R I, but six cases were positive for Fc gamma R II and III (not the same patients). These studies demonstrate that Ig Fc gamma R are acquired during normal differentiation in the BM at or before the level of colony-forming units. In addition, we show that acute leukemia cells commonly express Fc gamma R.

scholarly journals Expression of the three myeloid cell-associated immunoglobulin G Fc receptors defined by murine monoclonal antibodies on normal bone marrow and acute leukemia cells

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1951-1956 ◽  
Author(s):  
ED Ball ◽  
J McDermott ◽  
JD Griffin ◽  
FR Davey ◽  
R Davis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Monoclonal Antibodies ◽  
Acute Leukemia ◽  
Cell Sorting ◽  
Lymphoblastic Leukemia ◽  
Mononuclear Phagocytes ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Normal Bone Marrow ◽  
Normal Bone

Abstract Monoclonal antibodies (MoAbs) have been prepared recently that recognize the three cell-surface receptors for the Fc portion of immunoglobulin (Ig), termed Fc gamma RI (MoAb 32.2), Fc gamma R II (MoAb IV-3), and Fc gamma R III (MoAb 3G8) that are expressed on selected subsets of non-T lymphocyte peripheral blood leukocytes. In the blood, Fc gamma R I is expressed exclusively on monocytes and macrophages, Fc gamma R II on granulocytes, mononuclear phagocytes, platelets, and B cells, and Fc gamma R III on granulocytes and natural killer (NK) cells. We have examined the expression of these molecules on normal bone marrow (BM) cells and on leukemia cells from the blood and/or BM in order to determine their normal ontogeny as well as their distribution on leukemic cells. BM was obtained from six normal volunteers and from 170 patients with newly diagnosed acute leukemia. Normal BM cells were found to express Fc gamma R I, II, and III with the following percentages: 40%, 58%, and 56%, respectively. Cell sorting revealed that both Fc gamma R I and Fc gamma R II were detectable on all subclasses of myeloid precursors as early as myeloblasts. Cell sorting experiments revealed that 66% of the granulocyte-monocyte colony-forming cells (CFU-GM) and 50% of erythroid burst-forming units (BFU-E) were Fc gamma R II positive with only 20% and 28%, respectively, of CFU-GM and BFU-E were Fc gamma R I positive. Acute myeloid leukemia (AML) cells expressed the three receptors with the following frequency (n = 146): Fc gamma R I, 58%; Fc gamma R II, 67%; and Fc gamma R III, 26% of patients. Despite the fact that Fc gamma R I is only expressed on monocytes among blood cells, AML cells without monocytoid differentiation (French-American-British [FAB]M1, M2, M3, M6) were sometimes positive for this receptor. However, Fc gamma R I was highly correlated with FAB M4 and M5 morphology (P less than .001). Fc gamma R II was also correlated with FAB M4 and M5 morphology (P = .003). Cells from 11 patients with acute lymphoblastic leukemia were negative for Fc gamma R I, but six cases were positive for Fc gamma R II and III (not the same patients). These studies demonstrate that Ig Fc gamma R are acquired during normal differentiation in the BM at or before the level of colony-forming units. In addition, we show that acute leukemia cells commonly express Fc gamma R.

scholarly journals Loss of suppression of normal bone marrow colony formation by leukemic cell lines after differentiation is induced by chemical agents

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 100-106 ◽  
Author(s):  
HN Steinberg ◽  
AS Tsiftsoglou ◽  
SH Robinson
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Colony Formation ◽  
Leukemic Cell ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Cell Phenotype ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Leukemic Cell Lines

Abstract The human leukemic cell lines K562 and HL-60 were cocultured with normal bone marrow (BM) cells. Coculture with 10(4) K562 or HL-60 cells results in 50% inhibition of normal CFU-E and BFU-E colony formation. However, when the same number of K562 and HL-60 cells is first treated for two to five days with agents that induce their differentiation, a gradual loss in their capacity to inhibit CFU-E and BFU-E colony formation is observed. The inhibitory material in K562 cells is soluble and present in conditioned medium from cultures of these cells. The degree to which leukemic cell suppression of CFU-E and BFU-E growth is reversed is correlated with the time of exposure to the inducing agent. Suppression is no longer evident after five days of prior treatment with inducers. In fact, up to a 90% stimulation of CFU-E growth is observed in cocultures with K562 cells that have been pretreated with 30 to 70 mumol/L hemin for five days. K562 cells treated with concentrations of hemin as low as 30 mumol/L demonstrate increased hemoglobin synthesis and grow normally, but no longer have an inhibitory effect on CFU-E growth. Hence, reversal of normal BM growth inhibition must be caused by the more differentiated state of the K562 cells and not by a decrease in the number of these cells with treatment. Thus, induction of differentiation in cultured leukemic cells not only alters the malignant cell phenotype but also permits improved growth of accompanying normal marrow progenitor cells. Both are desired effects of chemotherapy.

scholarly journals Phenotypic heterogeneity of TDT+ cells in the blood and bone marrow: implications for surveillance of residual leukemia [see comments]

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 312-319
Author(s):  
RG Smith ◽  
RL Kitchens
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Normal Blood ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Hla Dr ◽  
Lineage Markers ◽  
Minimal Residual

Terminal deoxynucleotidyl transferase (TdT) is a useful marker for normal lymphocyte precursors and acute lymphoblastic leukemia (ALL). Our previous studies, however, have shown that for monitoring minimal residual disease in the circulation, assay for TdT alone is not sufficiently specific to distinguish leukemia cells from the background of rare normal blood TdT+ cells. In an attempt to increase specificity for leukemic cells, we have used double and triple immunophenotypic analysis to characterize normal circulating and bone marrow TdT+ cells. Overall, normal TdT+ cells were about 1000-fold more frequent in the marrow than in the blood. More than 75% of TdT+ cells in both the blood and marrow expressed the CD34, CD22, and HLA-DR antigens. However, circulating TdT+ cells infrequently expressed CD19 (4.5%) and CD9 (2.3%), compared with their marrow counterparts (74% and 47%, respectively). The brightly staining CD10+ phenotype, frequently associated with ALL blasts, was significantly less common among normal blood (5.7%) than marrow (31%) TdT+ cells. Although T-lineage markers were rarely expressed on TdT+ cells in either site, CD7+ cells were far more prevalent within the circulating TdT+ subset (4%) than among the marrow population (less than 0.2%). The results suggest a selective release of lineage-uncommitted and/or thymus-destined TdT+ cells from the marrow into the circulation. Moreover, since CD19, CD9, and high- density CD10 are frequently found on ALL blasts, staining for these markers on TdT+ cells in the circulation should improve the specificity of assay for residual common ALL cells. Likewise, assay for CD5+ and possibly CD7+ TdT+ cells in either marrow or blood should provide a very sensitive method of detection of T-ALL blasts.

Novel Multiparametric Quantitative Immunocytomorphological Characterisation of Human Bone Marrow Precursor Differentiation and of Haematopoietic Neoplasms Using ImageStream® Cytometry

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4871-4871
Author(s):  
Catherine Claude Martin ◽  
Chantal Jayat-Vignoles ◽  
Jean-Luc Faucher ◽  
Thaddeus George ◽  
Vidya Venkatachalam ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Blood Cells ◽  
High Speed ◽  
Tumour Cells ◽  
Leukemic Cells ◽  
Normal Bone Marrow ◽  
Normal Cells ◽  
Normal Bone ◽  
Abnormal Cells

Abstract The ImageStream technology performs high speed acquisition of brightfield, laser scatter and up to four fluorescent images per cell for several thousands of cells in suspension, thereby enabling simultaneous immunophenotyping and morphology-based measurements. This is the only technology combining cytology and flow cytometry in one single platform. Our aim was to study normal and tumour cells of the haematopoietic lineage with this new technology in order to improve diagnosis of haematological disorders. We have defined cytomorphological criteria of normal bone marrow (n=4) and circulating blood cells (n=40). Cells were multi-colour labelled with both DRAQ5 nuclear stain and CD45 ECD-mAb, and additionally labeled with a combination of mAbs against either CD3/CD19, CD11b/CD16, CD14/CRTH2, or CD71/CD235. Results for normal cells were compared to those obtained by classical cytometry and cytology. We then applied these criteria to samples with patients with circulating leukemic cells, including 1 myelodysplatic syndrome (MDS), 1 myeloproliferative syndrome (MPS), 3 acute lymphoblastic leukaemia (ALL), 2 follicular lymphomas (FL) and 20 chronic lymphocytic lymphomas (CLL). We have created completely new quantitative cytomorphological criteria for classifying blood cells using parameters that measure cellular size and shape, nuclear to cytoplasmic area ratio, nuclear lobe count, SSC texture, the ratio between the size and the major axis of CD45, the ratio between the intensity and the compactness of SSC signal, and the intensity of DRAQ5 labelling, to name a few. Using these criteria, we have characterised normal bone marrow differentiation and normal circulating blood cells. We have obtained a perfect correlation with classical cytology and flow cytometry. Analysis of pathological samples showed that abnormal cells were recognized in all cases. We found an abnormal blast cell compartment and an abnormal monocytic differentiation branch in the case of MDS. We have also defined specific cytomorphological properties that distinguish ALL, FL and CLL tumour cells from normal cells. We also provide data that enumerates the proportion of large cells, of atypical CLL cells and of cells in the G2/M phase. Altogether, these results show that a technology combining cytology and flow cytometry in a single platform leads to the discovery of completely new and quantitative cytomorphological parameters defining each stage of normal cell and each category of abnormal cells of the haematopoietic lineage, opening completely new perspectives for the diagnosis of haematopoietic neoplasms.

scholarly journals Oncogenesis of CRLF2 Overexpression and Effect of JAK2 Inhibitor in CRLF2 Overexpressed B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2757-2757
Author(s):  
Yan Gu ◽  
Chunhua Song ◽  
Sinisa Dovat ◽  
Qinglong Guo ◽  
Qinyu Ge ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Cell Proliferation ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cox Model ◽  
Lymphoblastic Leukemia ◽  
Normal Bone Marrow ◽  
Jak2 Inhibitor ◽  
Normal Bone

Backgroud: Cytokine receptor-like factor 2 (CRLF2) plays an important role in the development of normal B lymphocytes, which can mediate the proliferation of early B cells. However, the diect oncogenic effect of CRLF2 overexpression in acute lymhpoblastic leukemia (ALL) is far yet to be clarified. Here, we explored the effect of CRLF2 overexpression on cell proliferation and the effect of the novel JAK2 inhibitor on B-ALL cells with CRLF2 overexpression. Methods: The 83 patients with newly-diagnosed ALL (56 B-cell and 27 T-cell ALL; range from 14 to 77 years old) between June 2008 and June 2016 were studied at Zhongda Hospital Southeast University. The 21 normal bone marrow subjects were enrolled as controls. The qPCR method is developed for detection CRLF2 expression and the CRLF2 overexpression was determined with a cutoff value more than the highest sample of normal bone marrow control. Median differences between the cohorts were evaluated using a Mann-Whitney U-test. Frequency differences were analyzed using uni- and multivariate Cox model. Event-free survival (EFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared by log-rank test. CRLF2 F232C gain-of-function mutant which we previously reported or CRLF2 were expressed in Nalm6 and 697 B-ALL cells with lentiviral transduction. WST-1 cell proliferation assay and in vitro clonogenic assay were performed upon JAK2 inhibitor (BBT594) treatment. Nalm6-CRLF2-luc, Nalm6-F232C-luc, and Nalm6-vector-luc cells were injected via tail vein into the NSG mice. The leukemia engraftment was monitored once a week by living imaging. Results: The expression of CRLF2 in patietns with ALL was significantly higher than the normal control (P<0.0001). Patients with CRLF2 overexpression had a significantly higher WBC count (53*10^9/L vs. 29.5*10^9/L, P=0.041). Survival analysis showed that the patients with CRLF2 overexpression had a worse EFS and OS, the differences were statistically significant (11 months vs. 26 months, P=0.043 and 15 months vs. 32 months, P=0.015). Also, the CRLF2 expression is determined with flow cytometry after staining with FITC-CRLF2 antibody in 28 samples. The correlation analysis was performed on the CRLF2 expression detected by qPCR and flow cytometry, respectively. A significant positive correlation of the two methods was observed(r=0.957, P<0.0001). These data not only indicate that CRLF2 overexpression is a marker of poor outcome, but also reveal the qPCR might be a simple and quick method for screening CRLF2 overexpression in the clinic compared to flow cytometry which is commonly used. We further found that expression of CRLF2 or CRLF2 F232C mutant into Nalm6 and 697 B-ALL cells dramatically increase the CRLF2 mRNA level, which is 69 times than vector-only control. Moreover, CRLF2 or CRLF2 F232C significantly promotes the cell proliferation of Nalm6 and 697 cells compared to vector only (P<0.001). In addition, JAK2 inhibitor (BBT594) treatment showed the significant dose-dependent cell proliferation arrest and clonogenic inhibition in CRLF2 or CRLF2 F232C overexpressed Nalm6 and 697 cells compared to vector-only control. Furthermore, in vivo we observed the 5-fold higher signal intensity of leukemia engraftment in the mice injected with Nalm6-CRLF2-luc or Nalm6-F232C-luc compared to that of Nalm6-vector-luc control 1-3 weeks after the injection(P<0.001). The Nalm6-CRLF2-luc and Nalm6-F232C-luc infiltrations were observed in bone marrow, central nervous system, liver and spleen of the mice. Conclusion: We showed that CRLF2 overexpression could enhance the proliferation and infiltration of human B-ALL cells, and for the first time indicated that JAK2 inhibitor could suppress the cell proliferation and clonogenesis of the CRLF2 overexpressed B-ALL cells. Our data provide direct evidence of the oncogenic role of CRLF2 overexpression and the new therapeutic potential for targeting CRLF2 overexpressed B-ALL with JAK2 inhibitor. Disclosures No relevant conflicts of interest to declare.

scholarly journals Loss of suppression of normal bone marrow colony formation by leukemic cell lines after differentiation is induced by chemical agents

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 100-106
Author(s):  
HN Steinberg ◽  
AS Tsiftsoglou ◽  
SH Robinson
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Colony Formation ◽  
Leukemic Cell ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Cell Phenotype ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Leukemic Cell Lines

The human leukemic cell lines K562 and HL-60 were cocultured with normal bone marrow (BM) cells. Coculture with 10(4) K562 or HL-60 cells results in 50% inhibition of normal CFU-E and BFU-E colony formation. However, when the same number of K562 and HL-60 cells is first treated for two to five days with agents that induce their differentiation, a gradual loss in their capacity to inhibit CFU-E and BFU-E colony formation is observed. The inhibitory material in K562 cells is soluble and present in conditioned medium from cultures of these cells. The degree to which leukemic cell suppression of CFU-E and BFU-E growth is reversed is correlated with the time of exposure to the inducing agent. Suppression is no longer evident after five days of prior treatment with inducers. In fact, up to a 90% stimulation of CFU-E growth is observed in cocultures with K562 cells that have been pretreated with 30 to 70 mumol/L hemin for five days. K562 cells treated with concentrations of hemin as low as 30 mumol/L demonstrate increased hemoglobin synthesis and grow normally, but no longer have an inhibitory effect on CFU-E growth. Hence, reversal of normal BM growth inhibition must be caused by the more differentiated state of the K562 cells and not by a decrease in the number of these cells with treatment. Thus, induction of differentiation in cultured leukemic cells not only alters the malignant cell phenotype but also permits improved growth of accompanying normal marrow progenitor cells. Both are desired effects of chemotherapy.

scholarly journals Restricted Immunoglobulin Joining Chain (IgJ) Protein Expression in B Lymphoblastic Leukemia (B-ALL) Based on B-ALL Subtype

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-7
Author(s):  
Catherine K Gestrich ◽  
Kwadwo Asare Oduro
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Protein Expression ◽  
Hodgkin Lymphoma ◽  
Predictive Value ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Normal Bone Marrow ◽  
Neoplastic Cells ◽  
Normal Bone

Background Philadelphia-like (Ph-like) B Lymphoblastic Leukemia (B-ALL) is a high-risk subtype of B-ALL that lacks the BCR-ABL1 fusion but has a gene expression profile similar to Philadelphia positive (Ph+) B-ALL. Gene expression profiling has previously identified Immunoglobulin Joining chain (IgJ) overexpression at the mRNA level in Ph-like B-ALL. This is surprising since IgJ is normally expressed by mature or maturing B cells. The normal function of IgJ protein is to concatenate monomers of immunoglobulin IgM or IgA into the mature pentameric and dimeric forms of these molecules respectively. IgJ also plays a crucial role in transport of IgA protein across mucosal epithelium to facilitate mucosal humoral immunity. In hematopathology, J chain immunohistochemistry (IHC) has been used to identify neoplastic cells in nodular lymphocyte predominate Hodgkin lymphoma (NLPHL) and can be used in distinguishing this disease from morphologic mimickers. It does not have known diagnostic utility outside of this context. Lymphoblasts do not typically express immunoglobulins at the protein level. Therefore, we sought to determine the protein expression of IgJ in B-ALL and to determine whether IgJ immunohistochemistry may be employed in identifying particular subtypes of B-ALL. Methods We selected a total of 46 B-ALL cases diagnosed from a bone marrow sample at our institution from 2016-2019 with adequate diagnostic material for IHC. This included 5 cases of Ph-like B-ALL, all with a CRLF2 rearrangement and overexpression, 7 de novo Ph+ B-ALL and 34 cases representing the other most commonly recognized WHO subtypes of B-ALL, determined based on cytogenetic studies performed at the time of diagnosis. No cases of B-ALL with t(5;14) and B-ALL with iAMP21 was represented. Our cohort included 23 pediatric cases and 24 adult cases and the patients ranged from 1 to 82 years old at the time of initial diagnosis. A total of 8 normal bone marrow cases (negative staging bone marrow biopsies for diffuse large B cell lymphoma, neuroblastoma or classic Hodgkin lymphoma) were used as controls. IgJ IHC was performed on B-plus fixed paraffin embedded bone marrow biopsy specimens using a commercially available and validated anti-IgJ monoclonal antibody (clone OTI3B3). Staining of bone marrow samples was performed at 2 different dilutions; tonsil secondary follicles and neoplastic cells from NLPHL were used as technical controls. Cellular staining in the lymphoblasts was scored in a blinded manner by a board certified hematopathologist and a pathologist in training as diffusely positive, partially positive, or negative. Results Cellular staining was distinguishable from background staining due to circulating immunoglobulins and there was almost perfect inter-observer concordance in identifying positive and negative cases (agreement of 98%, kappa test 0.94). All normal bone marrow controls cases were negative for IgJ cellular staining. A total of 11/46 (23%) B-ALL cases demonstrated partial or diffuse cellular staining for IgJ in the lymphoblasts. This included 4/5 (80%) Ph-like cases, 5/7 (71%) Ph+ cases, 1/3 MLL rearranged cases and 1/6 ETV6-RUNX1. All TCF3-PBX1 (0/4), hyperdiploid B-ALL (0/10), hypodiploid B-ALL (0/2), and B-ALL, NOS cases (0/9) were negative for IgJ. Diffuse IgJ staining was restricted to Ph-like (2/4) or Ph+ (2/5) B-ALL subtypes; the positive MLL rearranged and ETV6-RUNX1 B-ALL cases only showed weak partial staining. IgJ protein was significantly expressed in Ph+/Ph-like B-ALL (p&lt;0.0001) and in our cohort, detected these cases with a 75% sensitivity, 95% specificity, 82% positive predictive value and 92% negative predictive value. Conclusion We conclude that IgJ protein expression occurs in a subset of B-ALL, predominantly restricted to Ph+ and Ph-like cases. Although, these findings will need to be validated in larger studies, our results suggest that IgJ IHC, in concert with routine standard cytogenetics studies may be a rapid and cost effective method in identifying Ph-like B-ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Dynamin inhibition causes context-dependent cell death of leukemia and lymphoma cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0256708
Author(s):  
Christopher von Beek ◽  
Linnéa Alriksson ◽  
Josefine Palle ◽  
Ann-Marie Gustafson ◽  
Mirjana Grujic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Acute Leukemia ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Tumor Formation ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Bone Marrow Biopsies

Current chemotherapy for treatment of pediatric acute leukemia, although generally successful, is still a matter of concern due to treatment resistance, relapses and life-long side effects for a subset of patients. Inhibition of dynamin, a GTPase involved in clathrin-mediated endocytosis and regulation of the cell cycle, has been proposed as a potential anti-cancer regimen, but the effects of dynamin inhibition on leukemia cells has not been extensively addressed. Here we adopted single cell and whole-population analysis by flow cytometry and live imaging, to assess the effect of dynamin inhibition (Dynasore, Dyngo-4a, MitMAB) on pediatric acute leukemia cell lines (CCRF-CEM and THP-1), human bone marrow biopsies from patients diagnosed with acute lymphoblastic leukemia (ALL), as well as in a model of lymphoma (EL4)-induced tumor growth in mice. All inhibitors suppressed proliferation and induced pronounced caspase-dependent apoptotic cell death in CCRF-CEM and THP-1 cell lines. However, the inhibitors showed no effect on bone marrow biopsies, and did not prevent EL4-induced tumor formation in mice. We conclude that dynamin inhibition affects highly proliferating human leukemia cells. These findings form a basis for evaluation of the potential, and constraints, of employing dynamin inhibition in treatment strategies against leukemia and other malignancies.

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