Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond

Abstract

Leukemias harboring mixed lineage leukemia (MLL1) gene abnormalities are associated with poor clinical outcomes and new therapeutic approaches are desperately needed. Rearrangement of the MLL1 gene generates chimeric proteins that fuse the NH3-terminus of MLL1 to the COOH-terminus of its translocation partners. These MLL1-fusion oncoproteins drive the expression of homeobox genes such as HOXA cluster genes and MEIS1, which are known to induce leukemic transformation of hematopoietic progenitors. Genome-wide histone methylation studies have revealed that the abnormal expression of MLL1-fusion target genes is associated with high levels of H3K79 methylation at these gene loci. The only known enzyme that catalyzes methylation of H3K79 is disruptor of telomeric-silencing 1-like (DOT1L). Loss-of-function mouse models as well as small molecular inhibitors of DOT1L demonstrate that leukemias driven by MLL1-translocations are dependent on DOT1L enzymatic activity for proliferation and for the maintenance of HOXA gene expression. Furthermore, DOT1L also appears to be important for HOXA gene expression in other settings including leukemias with select genetic abnormalities. These discoveries have established a foundation for disease-specific therapies that target chromatin modifications in highly malignant leukemias harboring specific genetic abnormalities. This review focuses on the molecular mechanisms underlying MLL1-translocation-driven leukemogenesis, and the latest progress on DOT1L-targeted epigenetic therapies for MLL1-rearranged and other leukemias.

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

“…289,290 Other examples are targeting of BRD4, a member of the BET family of bromodomain epigenetic readers, 291 or of KMT2A (MLL)-rearranged leukemias. 292,293 In a randomized trial conducted in patients with relapsed and refractory AML, the topoisomerase II inhibitor vosaroxin in combination with IDAC demonstrated a small survival benefit in patients older than 60 years (7.1 vs 5.0 months); a benefit was not shown in younger patients, potentially due to the higher transplant rate (45.8% ,60 years vs 20.2% $60 years). 222 Finally, targeted immunotherapy is an important novel approach.…”

Jmjd2/Kdm4 demethylases are required for expression ofIl3raand survival of acute myeloid leukemia cells

“…Mechanistic insight into the underlying molecular basis of leukemogenesis driven by MLL1 fusions has expanded significantly within recent years (Cai et al 2015;Chen and Armstrong 2015). Wild-type MLL1 is a histone methyltransferase with specificity toward H3K4 and is required for the transcription of 1.8% of mammalian genes, including members of the homeobox (HOX) gene cluster (Rao and Dou 2015).…”

“…Several chromatin-associated enzymes have been found to be required for the growth of MLL-rearranged leukemia, and small molecule inhibitors of some of these enzymes are promising candidates for the development of new drugs (Cai et al 2015;Chen and Armstrong 2015). The JMJD2 (also known as KDM4) enzymes are histone demethylases with specificity toward H3K9me3/me2 and H3K36me3/me2 (Cloos et al 2006;Fodor et al 2006;Klose et al 2006;Whetstine et al 2006).…”

SET/MLL family proteins in hematopoiesis and leukemia

“…These differences may underlie the fact that only MLL1 is involved in chromosomal translocations in leukemia. The mechanisms by which MLL-fusion oncoproteins transform cells have been reviewed extensively [56][57][58][59], but the contribution of the non-translocated, wildtype allele remains controversial. Several early studies suggested that the remaining wild-type MLL1 molecule was required for maintaining MLL-AF9 initiated leukemia or that targeting the HMT activity of MLL1 would be therapeutically beneficial [60,61].…”