Induction of Differentiation and Apoptosis— A Possible Strategy in the Treatment of Adult Acute Myelogenous Leukemia

Abstract

A differentiation block with accumulation of immature myeloid cells characterizes acute myelogenous leukemia (AML). However, native AML cells often show some morphological signs of differentiation that allow a classification into different subsets, and further differentiation may be induced by exposure to various soluble mediators, e.g., all trans-retinoic acid (ATRA) and several cytokines. Combination therapy with ATRA and chemotherapy should now be regarded as the standard treatment for the acute promyelocytic leukemia variant of AML. Several agents can induce leukemic cell differentiation for other AML subtypes, although these effects differ between patients. Differentiation may then be associated with induction of apoptosis, and differentiation-inducing therapy may therefore become useful in combination with intensive chemotherapy to increase the susceptibility of AML blasts to drug-induced apoptosis. However, it should be emphasized that differentiation and apoptosis can occur as separate events with different regulation in AML cells, and future studies in AML should therefore focus on: A) the identification of new agents with more predictable effects on differentiation and apoptosis; B) the use of clinical and laboratory parameters to define new subsets of AML patients in which differentiation/apoptosis induction has a predictable and beneficial effect, and C) further characterization of how AML blast sensitivity to drug-induced apoptosis is modulated by differentiation induction.

DOT1L Inhibitor EPZ-5676 Displays Synergistic Antiproliferative Activity in Combination with Standard of Care Drugs and Hypomethylating Agents inMLL-Rearranged Leukemia Cells

“…2). Induction of blast differentiation and/or apoptosis is an established approach to resolution of human leukemias (Bruserud et al, 2000;Nowak et al, 2009). The ability of EPZ-5676 to cause blast differentiation and apoptosis by itself, and the enhancement of these effects by Ara-C and daunorubicin, bode well for the effective use of this compound alone or with chemotherapy as a clinical treatment for MLL-r patients.…”

The Common Leukemic Fusions in Pathogenesis and in Treatment Response in Acute Myeloid Leukemia

“…The major treatment choice is the classical chemotherapy [10]. The M2 AML responds well to high dose cytarabine exhibiting high remission rate and long disease-free survival [57].…”

“…AML is characterized by accumulation of cells at the early stages of the differentiation process [8][9][10]. This is mostly attributed to dysfunctional regulatory transcription factors, resulting in aberrant gene expression and function [7,9].…”

“…The subtypes are denoted as M0-M7 [2,4,10,13]. The grouping is made based on the degree of granulocytic maturation (M1, M2, M3) or monocytic differentiation (M4 & M5) or presence of large number of erythroblasts (M6) or magakaryoblasts (M7) *Address correspondence to this author at the Clinical Research Cancer, Division of Experimental Cancer Research, Lund University, Malmö University Hospital, 205 02, Malmö, Sweden; Tel: +46-40-391106; Fax: +46-40-391222; E-mail: jenny_l.persson@med.lu.se [10,13]. The individual subtypes of this heterogenous disease can be identified using multiple methods such as cellular morphology, cytochemistry, immunophenotypes and molecular analysis [14].…”

Antimony-trioxide- and arsenic-trioxide-induced apoptosis in myelogenic and lymphatic cell lines, recruitment of caspases, and loss of mitochondrial membrane potential are enhanced by modulators of the cellular glutathione redox system

“…As 2 O 3 was established as a potent alternative in therapy of all-trans retinoic acid (ATRA)-resistant APL and shows, like Sb 2 O 3 , similar cellular effects to ATRA in APL: localization of the t(15;17) specific PML-RARα-fusion protein in nuclear bodies and degradation of the fusion protein [6][7][8][9] and induction of differentiation and apoptosis [10][11][12][13][14]. Lately, we showed that induction of apoptosis by As 2 O 3 in 22 myeloid and non-myeloid malignant cell lines of different sensitivity for cytostatic drugs, is based on breakdown of the mitochondrial membrane potential (Ψ m ) and therefore the redox system of the cell is one of the primary targets of As 2 O 3 .…”