Remodeling Chromatin in the Biology and Treatment of Acute Leukemia

Abstract

Therapy for acute leukemia has changed markedly over the past decade with the introduction of oncogene targeted therapy for certain subtypes, including acute promyelocytic leukemia (APML) and Philadelphia chromosome positive acute lymphoblastic leukemia, and better utilization of the graft-versus-leukemia effect in allotransplantation. New discoveries regarding the regulation of transcription by chromatin remodeling complexes has furthered our understanding of leukemia biology and shed light on the mechanisms behind some of our current therapies such as all-trans retinoic acid. Unlike chronic myeloid leukemia in which deregulation of a specific tyrosine kinase is responsible for driving the disease process, the majority of oncogenes involved in the pathogenesis of acute leukemia are abnormal fusion proteins acting as de-regulated transcription factors that prevent normal gene expression programs via chromatin mediated silencing. Many of these transcription factors are highly regulated in certain developmental compartments in normal physiology, but when aberrantly expressed, can block the differentiation of progenitor cells leading to leukemia. Targeted therapy with all trans-retinoic acid in acute promyelocytic leukemia, for example, disrupts the recruitment of histone deacetylases to transcriptional complexes and allows normal myeloid maturation to proceed. Ongoing studies into the biology of leukemia suggest that despite the number and diversity of cytogenetic abnormalities detected, leukemogenesis depends on a relatively small number of abnormal signaling pathways (such as the de-repression of core binding factor activity), many of which are involved in the restructuring of chromatin. Targeted therapy directed against specific chromatin remodifying activity offers great potential in the treatment of other subtypes of acute leukemia. Less specific chromatin remodeling therapies such as the histone deacetylase inhibitors which include valproate, trichomans A, thalidomide and butyrate have anti-leukemic activity in vitro in non-ATRA responsive leukemias and clinical trials with such agents are currently proceeding.