Differentiation therapy of myeloid leukemia: four decades of development

Abstract

Acute myeloid leukemia is characterized by arrested differentiation, and agents that overcome this block are therapeutically useful, as shown by the efficacy of all-trans retinoic acid in acute promyelocytic leukemia. However, the early promise of differentiation therapy did not translate into clinical benefit for other subtypes of acute myeloid leukemia, in which cytotoxic chemotherapeutic regimens remained the standard of care. Recent advances, including insights from sequencing of acute myeloid leukemia genomes, have led to the development of targeted therapies, comprising agents that induce differentiation of leukemic cells in preclinical models and clinical trials, thus rejuvenating interest in differentiation therapy. These agents act on various cellular processes including dysregulated metabolic programs, signaling pathways, epigenetic machinery and the cell cycle. In particular, inhibitors of mutant IDH1/2 and FLT3 have shown clinical benefit, leading to approval by regulatory bodies of their use. Besides the focus on recently approved differentiation therapies, this review also provides an overview of differentiation- inducing agents being tested in clinical trials or investigated in preclinical research. Combinatorial strategies are currently being tested for several agents (inhibitors of KDM1A, DOT1L, BET proteins, histone deacetylases), which were not effective in clinical studies as single agents, despite encouraging anti-leukemic activity observed in preclinical models. Overall, recently approved drugs and new investigational agents being developed highlight the merits of differentiation therapy; and ongoing studies promise further advances in the treatment of acute myeloid leukemia in the near future.

p53 Protein Isoform Profiles in AML: Correlation with Distinct Differentiation Stages and Response to Epigenetic Differentiation Therapy

“…Differentiation therapy has been considered a promising approach for the treatment of AML for several decades, inspired by the tremendous effect of all- trans retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia, as well as the extensive biological effects in acute myeloid leukemia cells in general [ 20 ]. However, despite the encouraging effects of several differentiation inducing agents like valproic acid (VPA) and ATRA alone and in combination in cellular models, clinical efficacy in non-acute promyelocytic leukemia remains moderate [ 21 , 22 , 23 ].…”

Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells

“…AML is characterized by a differentiation block leading to accumulation of highly proliferative immature myeloid blasts. Therefore, differentiation-based therapy is a promising approach for AML treatment [ 41 ]. We have previously shown that (pro-)electrophilic polyphenols and drugs can enhance monocyte/macrophage differentiation of AML cells triggered by active vitamin D derivatives or other agents, without inducing cytotoxicity [ 24 , 25 , 38 ].…”

One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies

“…Connecting glucose uptake indirectly to activation of epigenetic enzymes with dual activity, in AML, LSD1 stabilises the transcription factor GATA1 on protein level and epigenetically silences the GATA1 negative regulator C/EBPα, thus promoting glucose metabolism [ 323 ]. In haematological malignancies, e.g., AML, MDS, and CML, LSD1 contributes to leukaemogenesis [ 324 ].…”