Disordered epigenetic regulation in MLL-related leukemia

Abstract

Leukemias bearing rearrangements of chromosome 11q23 are of particular interest due to their unique clinical and biological characteristics. 11q23 abnormalities occur in up to 70 % of infant leukemias, and about 10 % of adult acute myelogenous leukemias (AML). Two major rearrangements of the MLL gene are found in MLL-related leukemia. The most common of these is balanced translocations in which the N-terminal portion of MLL is fused to the C-terminus of the translocation partner. To date, nearly 100 different chromosome bands have been described in rearrangements involving MLL, and more than 70 known fusion partners of MLL have been cloned and characterized at the molecular level. Another major aberration of the MLL gene creates a repeat within the N-terminal MLL resulting in an internal partial tandem duplication (PTD). As a consequence, an extra amino-terminus is added in-frame to full-length MLL, resulting in leukemogenic MLL-PTD. MLL-PTD occurs predominantly in myeloid dysplasia syndromes, secondary AML (s-AML), and de novo AML. The presence of an MLL rearrangement generally confers a poor prognosis. MLL fusions and MLL-PTD are transcriptional regulators that take control of targets normally controlled by MLL, with the clustered HOX homeobox genes as prominent examples. Several epigenetic regulators that modify DNA or histones have been implicated in MLL fusion driven leukemogenesis, including DNA methylation, histone acetylation, and histone methylation. Recently, the histone methyltransferase DOT1L, the bromodomain and extra-terminal (BET) family member BRD4, and the MLL-interacting protein Menin have emerged as important mediators of MLL fusion-mediated leukemic transformation. The clinical development of targeted inhibitors of these epigenetic regulators has heralded promise for the treatment of MLL fusion leukemia. Although the biological function and molecular mechanism for MLL-PTD remains largely unknown, based on the primary protein structure of MLL-PTD and the knowledge gained so far from MLL fusions, newly developed inhibitors of epigenetic regulators could potentially also prove effective in the treatment of MLL-PTD related leukemias.

Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal

“…MLL-PTD is another mutant form of MLL, which contains a partial tandem duplication of the MLL N terminus, with the duplicated breakpoints matching the BCR found in MLL translocations (exons 9-11). 22,27 Our study indicates that the CXXC domain is the part of the MLL N terminus responsible for the downregulation of RUNX1/CBFb. The CXXC domain of MLL is a cysteine-rich sequence containing 2 CGXCXXC repeats in its core region (1154-1194 aa), which adopts an extended crescent-like structure coordinating 2 zinc ions.…”

“…19 The human MLL gene is located on chromosome 11q23 and is often involved in chromosome translocations with various partner chromosomes, generating MLL fusion proteins. [20][21][22] More than 70 MLL fusion proteins have been documented in leukemia patients. 23,24 In almost all fusion proteins, MLL breaks within an 8.3-kb break point cluster region (BCR), 25 which results in the deletion of PHD finger region but also the maintenance of the MLL CXXC domain within the fusion protein.…”

“…27,28 MLL regulates many targets involved in self-renewal, proliferation, survival, and differentiation. 22,29,30 The most wellstudied targets are found in the HOXA gene cluster. MLL may bind to DNA or chromatin directly or be recruited to target loci by DNAbinding transcription factors.…”

The incidence and distribution characteristics of MLL rearrangements in Chinese acute myeloid leukemia patients by multiplex nested RT-PCR

“…The presence of MLL rearrangement generally confers a poor prognosis. Inhibitors of epigenetic regulators could potentially also prove effective in the treatment of MLL-PTD-related leukemia [22]. The fusion gene of MLL-PTD plays a critical role in the pathogenesis of M4 and M5 AML patients.…”

Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011

“…26,27 Thus, HIST1H2BD and HIST1H1E may be added to the growing list of acute leukemia-associated genes, for example DNMT3, EZH2, HOX family, and MLL, that 13 contribute to the leukemogenic process through deregulated CpG methylation or histone modification. [28][29][30][31] Among the other recurrent gene targets, most -CDKN2A, EBF1, ETV6, IKZF1, PAX5, RAG1, and TBL1XR1 -have been thoroughly discussed previously. 17,19,27,32,33 However, three of the presently identified gene targets, ADD3, ATP10A and PAN3, have been less emphasized in previous studies.…”