Molecular regulators of HOXA9 in acute myeloid leukemia

被引:25
作者
Aryal, Sajesan [1 ,2 ]
Zhang, Yang [3 ,4 ]
Wren, Spencer [1 ,2 ]
Li, Chunliang [3 ,4 ]
Lu, Rui [1 ,2 ]
机构
[1] Univ Alabama Birmingham, Div Hematol & Oncol, Birmingham, AL 39294 USA
[2] Univ Alabama Birmingham, ONeal Comprehens Canc Ctr, Birmingham, AL 39294 USA
[3] St Jude Childrens Res Hosp, Dept Tumor Cell Biol, 332 N Lauderdale St, Memphis, TN 38105 USA
[4] St Jude Childrens Res Hosp, Canc Biol Program, Ctr Comprehens Canc, 332 N Lauderdale St, Memphis, TN 38105 USA
关键词
acute myeloid leukemia; epigenetic regulators; gene regulation; HOXA9; pharmacological inhibitors; transcription factors; METHYLTRANSFERASE GENE EZH2; MENIN-MLL INTERACTION; BONE-MARROW-CELLS; ASXL1; MUTATIONS; HOMEOBOX GENES; HEMATOPOIETIC EXPRESSION; HOMEODOMAIN PROTEINS; CHROMATIN DOMAINS; SOMATIC MUTATIONS; H3K79; METHYLATION;
D O I
10.1111/febs.16268
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Dysregulation of the oncogenic transcription factor HOXA9 is a prominent feature for most aggressive acute myeloid leukemia cases and a strong indicator of poor prognosis in patients. Leukemia subtypes with hallmark overexpression of HOXA9 include those carrying MLL gene rearrangements, NPM1c mutations, and other genetic alternations. A growing body of evidence indicates that HOXA9 dysregulation is both sufficient and necessary for leukemic transformation. The HOXA9 mRNA and protein regulation includes multilayered controls by transcription factors (such as CDX2/4 and USF2/1), epigenetic factors (such as MLL-menin-LEDGF, DOT1L, ENL, HBO1, NPM1c-XPO1, and polycomb proteins), microRNAs (such as miR-126 and miR-196b), long noncoding RNAs (such as HOTTIP), three-dimensional chromatin interactions, and post-translational protein modifications. Recently, insights into the dynamic regulation of HOXA9 have led to an advanced understanding of the HOXA9 regulome and provided new cancer therapeutic opportunities, including developing inhibitors targeting DOT1L, menin, and ENL proteins. This review summarizes recent advances in understanding the molecular mechanisms controlling HOXA9 regulation and the pharmacological approaches that target HOXA9 regulators to treat HOXA9-driven acute myeloid leukemia.
引用
收藏
页码:321 / 339
页数:19
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