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تسجيل

Genetic and Epigenetic Alterations in Acute Myeloid Leukemia: Chromosomal Abnormalities – Retinoic Acid Receptor Rearrangements

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 , 942

2026-10-08

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A distinct subset of AML, acute promyelocytic leukemia (APL) or FAB M3, comprises approximately 10% of adult AML cases and is defined by the presence of a translocation involving the retinoic acid receptor-α (RARA) on chromosome 17q21. This results in a distinct phenotype characterized by a maturation arrest at the promyelocyte stage. RARs heterodimerize with retinoid X receptors (RXRs) to bind DNA at retinoic acid response elements, where they control gene expression during development and differentiation. In the majority of cases, RARA is fused with the PML gene on chromosome 15q22 as a consequence of t(15;17)(q22;q21). Other rare fusion partners include PML-like zinc finger (PLZF), nucleophosmin (NPM1), nuclear mitotic apparatus protein (NUMA1), and signal transducer and activator of transcription 5B (STAT5B). Each of these fusion partners has a self-association domain, similar to RXRs, and the fusion product interferes with expression of retinoic acid transcriptional targets.

In mouse models, transgenic expression of PML-RARA results in APL after a long myeloproliferative phase; the long latency period prior to leukemia development implies that cooperating mutations are typically required for full transformation. Introduction of the FLT3 ITD hastens APL onset in mice. Consistent with this finding, more than 35% of human patients with APL have FLT3-ITD mutations and nearly 20% have FLT3-TKD mutations. PML-RARA appears to have a dominant negative effect on RARα transcriptional function, as well as a role in DNA and chromatin modification, resulting in impaired myeloid differentiation. In addition, the fusion protein disrupts the organization of PML nuclear bodies, which are subcellular structures that are involved in a number of cell cycle, metabolic, and apoptotic regulatory pathways.