2009
DOI: 10.1182/blood-2008-12-197061
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Therapeutic targeting of MLL

Abstract: Treatment of hematologic malignancies is evolving from a uniform approach to targeted therapies directed at the underlying molecular abnormalities of disease. The mixed lineage leukemia (MLL) protooncogene is a recurrent site of genetic rearrangements in acute leukemias; and since its discovery in 1992, many advances have been made in understanding its role in leukemogenesis. A variety of MLL translocation partners have been described, and detailed structure/function studies have identified functional domains … Show more

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Cited by 100 publications
(96 citation statements)
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“…122 Another possibility is to directly target the MLL complex. 123 The MLL complex requires the proteins MEN1 and PSIP1 to interact with chromatin. Indeed, excision of Men1 potently inhibits the proliferation of MLL-MLLT3-transformed cells and Hoxa9 expression in mice, 124 and similarly, knockdown of Psip1 impaired Hoxa9 expression.…”
Section: Toward Targeted Therapymentioning
confidence: 99%
“…122 Another possibility is to directly target the MLL complex. 123 The MLL complex requires the proteins MEN1 and PSIP1 to interact with chromatin. Indeed, excision of Men1 potently inhibits the proliferation of MLL-MLLT3-transformed cells and Hoxa9 expression in mice, 124 and similarly, knockdown of Psip1 impaired Hoxa9 expression.…”
Section: Toward Targeted Therapymentioning
confidence: 99%
“…Small-molecule MI-2, which specifically blocks MLL-Menin interaction, can effectively reverse MLL fusion protein mediated leukemic transformation by down-regulating the expression of MLL fusion target genes required for transformation Disordered epigenetic regulation structure between MLL-PTD and WT MLL, newly developed drugs, such as I-BET or MI2 may also be effective for MLL-PTD leukemia, as SEC/BRD4 and Menin interactions could be critical for MLL-PTD function. Recent evidence has demonstrated a role for histone deacetylase and DNA methyltransferase inhibitors in leukemia mediated by the MLL-PTD [62]. In contrast to leukemic cells with MLL translocations, blasts with the MLL-PTD do not express the wild-type MLL protein from the contralateral unaffected allele.…”
Section: Recent Trials Of Epigenetic Therapy Targeting Mll Leukemiamentioning
confidence: 99%
“…Emerging treatments such as all-trans retinoic acid, vitamin D3, histone deacetylase, and DNA methyltransferase inhibitors may improve the clinical outcome of leukemia patients with 11q23/MLL rearrangement [48,49]. Understanding of MLL-related leukemogenesis will be helpful to develop novel therapeutic targets.…”
Section: Discussionmentioning
confidence: 99%