PML – Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia defined by the recurrent chromosomal translocation t(15;17)(q22;q21), which fuses the promyelocytic leukemia (PML; HGNC:9113) gene on chromosome 15 with the retinoic acid receptor alpha (RARA) gene on chromosome 17, producing the PML-RARα oncoprotein that blocks myeloid differentiation (PMID:9096691). This fusion is detected in over 90% of APL cases, establishing PML-RARα as the molecular hallmark of the disease and a reliable diagnostic marker ([PMID:1323928]). Variant and cryptic PML-RARα transcripts arising from atypical breakpoints in PML exons 3–6 or insertion events have been reported in <10% of patients, underscoring the need for combined cytogenetic, FISH, and RT-PCR approaches for accurate detection ([PMID:20359255]).

Case series have documented that alternative three-way and four-way translocations involving chromosomes 2, 6, 12, 16, and 20 create PML-RARα fusions at ectopic loci without altering the leukemic phenotype, confirming that PML-RARα formation, rather than specific breakpoint localization, is the critical leukemogenic event ([PMID:10913680]). Moreover, PML-RARα fusion isoforms (bcr1, bcr2, bcr3) correlate with clinical variables such as white blood cell count and co-occurring FLT3-ITD mutations, which influence prognosis and guide risk-adapted therapy ([PMID:16029447]).

Experimental models demonstrate that PML-RARα disrupts PML nuclear bodies (NBs), sequesters nuclear corepressors, and exerts dominant-negative effects on wild-type PML and RARα, establishing a mechanistic basis for APL pathogenesis ([PMID:11050004]). Site-directed mutations in the PML RBCC domain impair NB assembly and sensitivity to arsenic trioxide (ATO), elucidating acquired drug resistance mechanisms in relapsed APL ([PMID:9378769]).

Transgenic mice expressing PML-RARα develop APL-like disease with long latency, accelerated by co-expression of activated FLT3, modeling cooperative oncogenic events in human APL. Combined all-trans retinoic acid (ATRA) and ATO therapy induces differentiation, restores PML NB integrity, and degrades PML-RARα, yielding high remission rates and establishing the current standard of care ([PMID:12515727]).

Collectively, the PML–APL association meets ClinGen criteria for a Definitive gene-disease relationship based on consistent cytogenetic findings in thousands of patients, robust functional concordance, and therapeutic targeting of the PML-RARα oncoprotein. Key Take-home: detection of PML-RARA fusion is essential for prompt APL diagnosis and informs curative ATRA/ATO therapy.

References

• Leukemia • 1997 • Variant complex translocations involving chromosomes 1, 9, 9, 15 and 17 in acute promyelocytic leukemia without RAR alpha/PML gene fusion rearrangement. PMID:9096691
• American Journal of Hematology • 1992 • Frequent rearrangements of retinoic acid receptor alpha gene and myl gene, and rare mutations of RAS and FMS genes in acute promyelocytic leukemia. PMID:1323928
• Blood • 1992 • Correlation of CD2 expression with PML gene breakpoints in patients with acute promyelocytic leukemia. PMID:1353379
• Blood • 2009 • Hidden abnormalities and novel classification of t(15;17) acute promyelocytic leukemia (APL) based on genomic alterations. PMID:19109227
• Blood • 2000 • Altered ligand binding and transcriptional regulation by mutations in the PML/RARalpha ligand-binding domain arising in retinoic acid-resistant patients with acute promyelocytic leukemia. PMID:11050004
• Blood • 2003 • A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657. PMID:12515727

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