تسجيل الدخول

تسجيل

Genetic and Epigenetic Alterations in Acute Myeloid Leukemia: Chromosomal Abnormalities – Mixed-Lineage Leukemia

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P942

2026-10-08

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Gene Rearrangements Translocations in the MLL1 gene (also known as KMT2A) are seen in up to 10% of patients with AML. MLL1 rearrangements are common in tAML following exposure to topoisomerase II inhibitors and are enriched in cases with the FAB M5a phenotype. Wild-type MLL1 binds DNA and methylates histone H3K4 via its C-terminal SET domain and regulates expression of target genes, including homeobox (HOX) genes. Members of the homeobox A cluster, including HOXA7 and HOXA9, play critical roles in the regulation of hematopoiesis and are normally expressed in early hematopoietic cells.

Rearranged MLL1 retains its N-terminal DNA-binding domain, whereas the C-terminal portion is replaced by a fusion partner. More than 70 unique fusion partners have been identified, including AF4, AF9, AF10, ELL, and ENL; these can interact with and recruit the his tone methyltransferase enzyme “disruption of telomeric silencing 1-like” (DOT1L), which methylates H3K79 and results in the expression of HOXA genes implicated in leukemic transformation. Expression of the MLL1-AF9 fusion in mice generates AML with high penetrance and short latency. The oncogenic function of these fusion proteins requires interaction with Menin, a protein encoded by MEN1 that binds to the N-terminus of MLL1. Inhibition of the Menin/MLL interaction represents a promising new avenue for drug development in AML.

Another mechanism by which MLL1 plays a role in leukemia is through an in-frame partial tandem duplication (MLL1-PTD). Mouse knock-in models with MLL1-PTD develop acute leukemias characterized by overexpression of Hox genes and an increase in H3/ H4 acetylation with associated H3K4 methylation.