Abstract
SummaryOne of the key features of acute myeloid leukemia (AML) is the arrest of differentiation at the early progenitor stage of myelopoiesis. Therefore, the identification of new agents that could overcome this differentiation block and force leukemic cells to enter the apoptotic pathway is essential for the development of new treatment strategies in AML. Regarding this, herein we report the pro-differentiation activity of the pan-Bcl-2 inhibitor, obatoclax. Obatoclax promoted differentiation of human AML HL-60 cells and triggered their apoptosis in a dose- and time-dependent manner. Importantly, obatoclax-induced apoptosis was associated with leukemic cell differentiation. Moreover, decreased expression of Bcl-2 protein was observed in obatoclax-treated HL-60 cells. Furthermore, differentiation of these cells was accompanied by the loss of their proliferative capacity, as shown by G0/G1 cell cycle arrest. Taken together, these findings indicate that the anti-AML effects of obatoclax involve not only the induction of apoptosis but also differentiation of leukemic cells. Therefore, obatoclax represents a promising treatment for AML that warrants further exploration.
Highlights
Acute myeloid leukemia (AML) is a hematological malignancy in which the bone marrow is replaced by a clonal population of abnormal myeloid progenitors [1]
We show for the first time that obatoclax, a pan-B cell lymphoma-2 (Bcl-2) inhibitor, promotes differentiation of human AML HL-60 cells accompanied by cell cycle arrest and the downregulation of Bcl-2 protein levels
Exposure of HL-60 cells to Obatoclax mesylate (OBAT) resulted in morphological changes characteristic of differentiation to the granulocytic lineage, such as reduced cytoplasmic basophilia, reduced nuclear/ cytoplasmic ratio and the appearance of condensed and lobulated nuclei; all cells fulfilling this criteria were considered to be in the process of differentiation (Fig. 1a)
Summary
Acute myeloid leukemia (AML) is a hematological malignancy in which the bone marrow is replaced by a clonal population of abnormal myeloid progenitors [1]. The major feature of AML is differentiation arrest of these progenitor cells at early stages of myelopoiesis. This is further accompanied by enhanced cell proliferation and resistance to death-inducing signals. AML is a disorder of impaired hematopoietic cell differentiation and apoptosis. Therapies aimed at resuming the process of maturation and apoptosis in leukemic cells are currently the most promising anti-AML strategies [1]. Treatment of acute promyelocytic leukemia (APL), a subtype of AML, with all-trans-retinoic acid (ATRA) was the first model of differentiation-targeted therapy [2]. Most non-APL AML patients do not benefit from ATRA therapy.
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