RARA – Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia defined by chromosomal rearrangements involving the retinoic acid receptor alpha gene (RARA) at 17q21. The prototypical event is the reciprocal translocation t(15;17)(q22;q21) generating the PML::RARA fusion oncogene, which is detectable in over 90% of APL cases and serves as a diagnostic hallmark (PMID:23363773).

Genetically, PML::RARA fusions account for the majority of APL presentations, with variant RARA fusion partners—including IRF2BP2, STAT5B, ZBTB16, NUP98, and FIP1L1—identified in approximately 5% of cases (PMID:15899384; PMID:25583766). Somatic point mutations within the ligand-binding domain (E-domain) of RARA, such as c.815G>A (p.Arg272Gln), have been documented in relapsed or ATRA-resistant APL, underscoring the spectrum of RARA alterations (PMID:9657734).

The PML::RARA fusion protein exerts dominant-negative repression of RARα target genes by aberrant recruitment of co-repressors and disruption of PML nuclear bodies; pharmacologic doses of all-trans retinoic acid (ATRA) relieve this repression, driving terminal myeloid differentiation and remission (PMID:11050004; PMID:9694705). Mutations in the RARA E-domain that diminish ligand binding or co-activator recruitment confer clinical resistance to ATRA, as demonstrated by in vitro differentiation assays and patient relapse specimens (PMID:9657734).

No significant contradictory genetic data have emerged; variant RARA rearrangements uniformly present with the APL phenotype and respond variably to ATRA and arsenic trioxide. Comprehensive cytogenetic, FISH, and molecular assays remain essential to detect canonical and cryptic RARA fusions, ensuring accurate diagnosis and risk stratification.

Key Take-home: RARA alterations—primarily the PML::RARA fusion—are definitive drivers of APL pathogenesis and critical biomarkers for diagnosis and targeted ATRA-based therapy.

References

• Cancer Genetics and Cytogenetics • 2000 • A PML/RARA chimeric gene on chromosome 2 in a patient with acute promyelocytic leukemia (M3) associated with a new variant translocation: t(2;15;17)(q21;q22;q21). PMID:10913680
• Acta haematologica • 2013 • An unusual cytogenetic rearrangement originating from two different abnormalities in chromosome 6 in a child with acute promyelocytic leukemia. PMID:23363773
• Cancer genetics and cytogenetics • 2005 • Acute promyelocytic leukemia with PML-RARA fusion on i(17q) and therapy-related acute myeloid leukemia. PMID:15899384
• Journal of the National Comprehensive Cancer Network : JNCCN • 2015 • Identification of a novel fusion gene, IRF2BP2-RARA, in acute promyelocytic leukemia. PMID:25583766
• Blood • 1998 • Mutations in the E-domain of RAR portion of the PML/RAR chimeric gene may confer clinical resistance to all-trans retinoic acid in acute promyelocytic leukemia. PMID:9657734
• 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

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