Differentiation therapy of leukemia: 3 decades of development

Abstract

IntroductionA characteristic abnormality of leukemia cells is that they are blocked at an early stage of their development and fail to differentiate into functional mature cells. During the 1970s and 1980s, several scientific achievements popularized the strategy of inducing malignant cells to overcome their block of differentiation and enter the apoptotic pathways as an elegant alternative to killing cancer cells by cytotoxic therapies. This intervention could theoretically limit exposure to unwanted side effects of cytotoxic chemotherapy, and more importantly, improve complete remission and cure rates. Pioneering reports included studies demonstrating the differentiating capability of dimethylsulfoxide (DMSO) on erythropoiesis, 1 efforts to elucidate substances to control the differentiation of myeloid leukemia, 2 and the first evidence of the differentiating properties of retinoic acid. 3,4 The initial promising preclinical results of this approach prompted a review article by us 25 years ago concerning the possibilities and therapeutic implications of differentiation induction in leukemia. 5 At that stage, cell line models for in vitro differentiation experiments were described. Substances such as phorbol diesters, teleocidins, polar planar drugs, cytokines, retinoids, and vitamin D metabolites showed dramatic potential to differentiate cell lines such as HL-60, KG-1, ML-3, or K562 in vitro and fueled the hope of developing a new approach to treat cancers by overcoming their blocked differentiation. Today, 25 years later, we discuss the progress and the clinical achievements of this therapeutic approach. Ligands of nuclear hormone receptorsPoster child of success: complete remissions of APL by differentiation therapyThe potential for differentiating therapy to improve cure rates in leukemia is exemplified by the development of all-trans retinoic acid (ATRA) for the targeted treatment of acute promyelocytic leukemia (APL). One of the most remarkable results of initial in vitro experiments was achieved in differentiating HL-60 cells with ATRA, which produced terminal differentiation in 90% of cells with 10 Ϫ6 M retinoic acid. 3 Investigators soon realized that ATRA was specifically effective in APL cells carrying a typical chromosomal translocation between chromosomes 15 and 17 [t(15;17)(q22; q21)] 6 but not in other leukemias. 4 The first APL patients treated with ATRA in the early 1980s achieved encouraging remissions by the new therapy. [7][8][9][10] The first clinical trial of ATRA reported 16 newly diagnosed, and 8 anthracycline refractory patients who were induced with single-agent ATRA. Complete hematologic remission was induced in all patients; more than 90% of samples from these individuals demonstrated in vitro evidence of blast differentiation. 10 This seminal trial changed the management and prognosis of APL, and introduced a paradigm for success of cell differentiation therapy. Subsequently, APL therapy was improved stepwise through elucidation of the most effective combination regimen of ATRA wit...

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.…”

Bortezomib Sensitizes Human Acute Myeloid Leukemia Cells to All-Trans-Retinoic Acid–Induced Differentiation by Modifying the RARα/STAT1 Axis

“…1A) sparked intensive differentiation therapy research (1). However, differentiation therapy is limited because ATRA is the sole efficient agent for differentiation-based therapy.…”

EGFR inhibitors exacerbate differentiation and cell cycle arrest induced by retinoic acid and vitamin D3in acute myeloid leukemia cells

“…Third, differentiation-stimulating agents should stimulate the transition of leukemic (stem) cells to a mature phenotype, thereby abolishing their proliferative potential and allowing them to undergo terminal differentiation-associated cell death. [3][4][5] A prominent example of such a differentiation therapy is all-trans retinoic acid (ATRA), the biologically active variant of vitamin A, which has been successfully employed for decades in the treatment of acute promyelocytic leukemia (APL). 6 Similarly, 1α,25-hydroxycholecalciferol, the active form of vitamin D 3 (VD) also known as calcifediol, and many of its analogs can stimulate the terminal differentiation of leukemic cell lines as well as primary myeloid precursors, and their therapeutic value has been tested in different clinical trials.…”