Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation

Imatinib mesylate (STI571) is a promising new treatment for chronic myelogenous leukemia (CML). The effect of imatinib mesylate on primitive malignant progenitors in CML has not been evaluated, and it is not clear whether suppression of progenitor growth represents inhibition of increased proliferation, induction of apoptosis, or both. We demonstrated here that in vitro exposure to concentrations of imatinib mesylate usually achieved in patients (1-2 μM) for 96 hours inhibited BCR/ABL-positive primitive progenitors (6-week long-term culture–initiating cells [LTCICs]) as well as committed progenitors (colony-forming cells [CFCs]). No suppression of normal LTCICs and significantly less suppression of normal CFCs were observed. A higher concentration of imatinib mesylate (5 μM) did not significantly increase suppression of CML or normal LTCICs but did increase suppression of CML CFCs, and to a lesser extent, normal CFCs. Analysis of cell division using the fluorescent dye carboxyfluorescein diacetate succinimidyl ester indicated that imatinib mesylate (1-2 μM) inhibits cycling of CML primitive (CD34+CD38−) and committed (CD34+CD38+) progenitors to a much greater extent than normal cells. Conversely, treatment with 1 to 2 μM imatinib mesylate did not significantly increase the percentage of cells undergoing apoptosis. Although a higher concentration of imatinib mesylate (5 μM) led to an increase in apoptosis of CML cells, apoptosis also increased in normal samples. In summary, at clinically relevant concentrations, imatinib mesylate selectively suppresses CML primitive progenitors by reversing abnormally increased proliferation but does not significantly increase apoptosis. These results suggest that inhibition of Bcr-Abl tyrosine kinase by imatinib mesylate restores normal hematopoiesis by removing the proliferative advantage of CML progenitors but that elimination of all CML progenitors may not occur.

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In vitro studies of the combination of imatinib mesylate (Gleevec) and arsenic trioxide (Trisenox) in chronic myelogenous leukemia

Experimental Hematology ◽

10.1016/s0301-472x(02)00836-6 ◽

2002 ◽

Vol 30 (7) ◽

pp. 729-737 ◽

Cited By ~ 73

Author(s):

Paul La Rosée ◽

Kara Johnson ◽

Michael E O'Dwyer ◽

Brian J Druker

Keyword(s):

Arsenic Trioxide ◽

Imatinib Mesylate ◽

Chronic Myelogenous Leukemia ◽

In Vitro Studies ◽

Myelogenous Leukemia

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Imatinib mesylate-induced long-term remission in extra-medullary T-cell lymphoid blastic phase of chronic myelogenous leukemia

Leukemia & Lymphoma ◽

10.1080/10428190600879995 ◽

2006 ◽

Vol 47 (11) ◽

pp. 2427-2430 ◽

Cited By ~ 2

Author(s):

Jan A. Burger ◽

Annette Schmitt-Gräff ◽

Andrea Bürkle ◽

Lysann Seiler ◽

Jürgen Finke

Keyword(s):

T Cell ◽

Imatinib Mesylate ◽

Chronic Myelogenous Leukemia ◽

Myelogenous Leukemia ◽

Blastic Phase

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Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies

Hematology ◽

10.1182/asheducation.v2000.1.90.90 ◽

2000 ◽

Vol 2000 (1) ◽

pp. 90-109 ◽

Cited By ~ 1

Author(s):

Hagop Kantarjian ◽

Junia V. Melo ◽

Sante Tura ◽

Sergio Giralt ◽

Moshe Talpaz

Keyword(s):

Stem Cell ◽

Tyrosine Kinase ◽

Chronic Myelogenous Leukemia ◽

Cytosine Arabinoside ◽

Myelogenous Leukemia ◽

Cell Transplant ◽

Abl Tyrosine Kinase ◽

Early Results ◽

Donor Lymphocyte Infusions

Abstract Over the last 2 decades, four major therapeutic approaches have drastically changed the prognosis in chronic myelogenous leukemia (CML): 1) allogeneic stem cell transplant (SCT); 2) interferon alpha (IFN-α) based regimens; 3) donor lymphocyte infusions (DLI); and 4) and the revolutionary BCR-ABL tyrosine kinase inhibitors such as STI571 (signal transduction inhibitor 571). Each modality has exploited and targeted different aspects of CML biology, and is associated with different risk-benefit ratios. In Section I of this review, Dr. Melo reviews the molecular pathophysiology of CML and potential new targets for therapy including anti-sense strategies to disrupt the BCR-ABL gene and inhibition of the BCR-ABL tyrosine kinase activity. In Section II, Dr. Tura, addresses important questions in the use of IFN-α for the treatment of CML, including the mechanism of action and the development of resistance, the optimal dose and duration of therapy and the prediction of response based on clinical features. An approach to the choice of therapy based on the predicted mortality is presented. In Section III Dr. Giralt presents an update on the results of unrelated donor transplantion, donor lymphocyte infusions (DLI) and non-ablative stem cell transplantation (NST) in CML. The roles of CD8-depletion, dose escalation and the transduction of suicide genes in treatment with DLI are addressed. Early results of NST in CML show that it is feasible and can result in long-term disease control. In Section IV Drs. Kantarjian and Talpaz review the results of IFN-α plus low-dose cytosine arabinoside and other promising modalities for CML including homoharringtonine, decitabine, and polyethylene glycol-interferon. In Section V they present an update on the recent experience with STI571. Objective but transient responses have been seen in 40% to 50% of patients in CML blastic phase. In accelerated phase, the response rate with STI571 exceeds 70%, and these responses are durable. In chronic phase CML, STI571 at 300 mg daily in patients who failed IFN-α produces a complete hematologic response (CHR) in over 90% of patients. Early results suggest cytogenetic response rates of approximately 50%, which may be major in approximately 30%. The maturing results with STI571 may soon change current recommendations regarding the relative roles of established modalities such as allogeneic SCT and IFN-α. Important questions include 1) whether STI571 therapy alone may be sufficient to induce long-term survival and event-free survival in CML, or whether it needs to be combined simultaneously or sequentially with IFN-α and cytosine arabinoside; and 2) what should the indications for frontline allogeneic SCT be in relation to STI571 therapy.

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Selective induction of apoptosis in Philadelphia chromosome-positive chronic myelogenous leukemia cells by an inhibitor of BCR–ABL tyrosine kinase, CGP 57148

Cell Death and Differentiation ◽

10.1038/sj.cdd.4400400 ◽

1998 ◽

Vol 5 (8) ◽

pp. 710-715 ◽

Cited By ~ 96

Author(s):

Shingo Dan ◽

Mikihiko Naito ◽

Takashi Tsuruo

Keyword(s):

Tyrosine Kinase ◽

Chronic Myelogenous Leukemia ◽

Philadelphia Chromosome ◽

Myelogenous Leukemia ◽

Leukemia Cells ◽

Abl Tyrosine Kinase ◽

Induction Of Apoptosis ◽

Chronic Myelogenous Leukemia Cells ◽

Philadelphia Chromosome Positive

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Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia

Stem Cells and Development ◽

10.1089/scd.2016.0262 ◽

2017 ◽

Vol 26 (9) ◽

pp. 656-677 ◽

Cited By ~ 9

Author(s):

Anna Chorzalska ◽

Javier Flores Kim ◽

Karim Roder ◽

Alexander Tepper ◽

Nagib Ahsan ◽

...

Keyword(s):

Imatinib Mesylate ◽

Chronic Myelogenous Leukemia ◽

Hippo Pathway ◽

Myelogenous Leukemia

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Bone Marrow-Derived, BCR/ABL+ and Flk1+CD31−CD34− Stem Cells from CML Patients That Are Insensitive to STI571 In Vitro.

Blood ◽

10.1182/blood.v106.11.4853.4853 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4853-4853

Author(s):

Yongping Song ◽

Baijun Fang ◽

Yanli Zhang ◽

Xudong Wei ◽

Lulu Lu ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Myelogenous Leukemia ◽

Short Term ◽

Abl Tyrosine Kinase ◽

Dividing Cells ◽

Almost All ◽

Proliferative Advantage

Abstract To evaluate the effect of imatinib mesylate (STI571, Gleevec) on primitive/committed malignant progenitor cells in chronic myelogenous leukemia (CML) and to further elucidate the mechanisms involved in CML relapse, bone marrow-derived, malignant, BCR/ABL+Flk1+CD31CD34− cells with hemangioblastic characteristics from CML patients were labeled with carboxy-fluorescein diacetate succinimidyl diester dye to enable high-resolution tracking of cell division. Then they were cultured in Methocult GF+ media with or without STI571. After culture, the cells were separated by fluorescence-activated cell sorting into populations of viable quiescent versus cycling cells. Then the mechanisms involved in CML stem cells that became resistant to STI571 were studied. We found that in the most sensitive cases, STI571 killed almost all dividing cells; however, a significant population of viable BCR/ABL-positive cells were recovered in the undivided peak and confirmed to be the leukemic stem cells. STI571 also appeared to exhibit antiproliferative activity on the quiescent population. We further demonstrate that apoptosis was restricted to dividing cells, whereas nonproliferating BCR/ABL+Flk1+CD31CD34− cells were resistant to apoptosis induced by imatinib, Ara-C, VP-16, ceramide, or arsenic, either alone or in combination. These studies suggested that CML primitive stem cells remain viable in the presence of STI571 and that inhibition of BCR/ABL tyrosine kinase by STI571 restores normal hematopoiesis by removing the proliferative advantage of CML committed progenitors but that elimination of all CML progenitors may not occur. So despite dramatic short-term responses in vivo, such in vitro insensitive to STI571, might translate into disease relapse after prolonged therapy.

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