Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations

Dorrance, Adrienne M.; Liu, Shujun; Yuan, Weifeng; Becknell, Brian; Arnoczky, Kristy J.; Guimond, Martin; Strout, Matthew P.; Feng, Lan; Nakamura, Tatsuya; Yu, Li; Rush, Laura J.; Weinstein, Michael; Leone, Gustavo; Wu, Lizhao; Ferketich, Amy K.; Whitman, Susan P.; Marcucci, Guido; Caligiuri, Michael A.

doi:10.1172/jci25546

Cited by 112 publications

(99 citation statements)

References 40 publications

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“…These two findings suggest that MLL-PTD pathway(s) of leukemic transformation are different from those resulting from the fusion of MLL with partners other than itself. Murine knock-in models that express MLL-PTD show Hoxa9 but not Meis1 upregulation [44]. Our recent data show that murine MLL-PTD HSPCs exhibit elevated apoptosis at steady state, but become proliferative and resistant to apoptosis when exposed to stresses.…”

Section: Disordered Epigenetic Regulation In Mll-ptdmentioning

confidence: 70%

Disordered epigenetic regulation in MLL-related leukemia

et al. 2012

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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.

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Section: Disordered Epigenetic Regulation In Mll-ptdmentioning

confidence: 70%

Disordered epigenetic regulation in MLL-related leukemia

et al. 2012

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“…38 Finally, there is a direct link between MLL alterations and HOXA9 expression. [39][40][41][42][43][44] As predicted, upregulation of HOXA genes, especially HOXA9, suggests that increased selfrenewal and stem cell features are prominent in MYST3-linked AMLs (see Argiropoulos and Humphries for review 45 ). This is also the case of AMLs with NPM1 mutation, and it is noticeable that three cases clustering with MYST3-linked AMLs in cluster IIa showed NPM1 mutation.…”

Section: Myb Hox and Myst3-linked Amlsmentioning

confidence: 82%

Genome profiling of acute myelomonocytic leukemia: alteration of the MYB locus in MYST3-linked cases

Murati¹,

Gervais²,

Carbuccia³

et al. 2008

Leukemia

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The t(8;16)(p11;p13) is a rare translocation involved in de novo and therapy-related myelomonocytic and monocytic acute leukemia. It fuses two genes encoding histone acetyltransferases (HATs), MYST3 located at 8p11 to CREBBP located at 16p13. Variant translocations involve other HAT-encoding genes such as EP300, MYST4, NCOA2 or NCOA3. MYST3-linked acute myeloid leukemias (AMLs) share specific clinical and biological features and a poor prognosis. Because of its rarity, the molecular biology of MYST3-linked AMLs remains poorly understood. We have established the genome and gene expression profiles of a multicentric series of 61 M4/M5 AMLs including 18 MYST3-linked AMLs by using array comparative genome hybridization (aCGH) (n ¼ 52) and DNA microarrays (n ¼ 44), respectively. We show that M4/5 AMLs have a variety of rare genomic alterations. One alteration, a gain of the MYB locus, was found recurrently and only in the MYST3-linked AMLs (7/18 vs 0/34). MYST3-AMLs have also a specific a gene expression profile, which includes overexpression of MYB, CD4 and HOXA genes. These features, reminiscent of T-cell acute lymphoid leukemia (ALL), suggest the targeting of a common T-myeloid progenitor.

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“…219 Acute leukemias carrying MLL rearrangements also display induction of HOX genes, possibly due to direct binding of MLL fusion proteins to HOX promoters. 220 Such LSC can be triggered to proliferate after class I mutations.…”

Section: Gene Mutations In Acute Myeloid Leukemiamentioning

confidence: 99%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

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Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

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Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations

Cited by 112 publications

References 40 publications

Disordered epigenetic regulation in MLL-related leukemia

Disordered epigenetic regulation in MLL-related leukemia

Genome profiling of acute myelomonocytic leukemia: alteration of the MYB locus in MYST3-linked cases

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

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