Molecular biology of acute promyelocytic leukemia
- Wendy Stock, MD
Wendy Stock, MD
- Professor of Medicine
- Pritzker School of Medicine of the University of Chicago
- Michael J Thirman, MD
Michael J Thirman, MD
- Associate Professor of Medicine
- Pritzker School of Medicine of the University of Chicago
Acute myeloid leukemia (AML) refers to a group of hematopoietic neoplasms involving cells committed to the myeloid lineage. Acute promyelocytic leukemia (APL) is a biologically and clinically distinct variant of AML. APL was classified as AML-M3 in the older French-American-British (FAB) classification system and is currently classified as acute promyelocytic leukemia with t(15;17)(q24.1;q21.1);PML-RARA in the WHO classification system . (See "Classification of acute myeloid leukemia".)
The cytogenetic hallmark of APL is a translocation involving the retinoic acid receptor-alpha (RAR-alpha, RARa) locus on chromosome 17 . The vast majority of these cases contain t(15;17)(q24.1;q21.1), although several variant translocations involving RARa have been identified, including t(11;17) and t(5;17) [3-5]. Distinguishing between these translocations is important because patients with the variant translocation t(11;17) are almost invariably resistant to ATRA [3,4,6]. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)
The molecular biology of APL will be discussed here. The molecular biology of acute myeloid leukemias other than APL and of ALL is discussed separately. (See "Pathogenesis of acute myeloid leukemia" and "Cytogenetics and molecular genetics in acute lymphoblastic leukemia" and "Molecular genetics of acute myeloid leukemia".)
RETINOIC ACID AND THE RETINOIC ACID RECEPTOR
Retinoic acid is a critical ligand in the differentiation pathway of multiple tissues, mediated through binding to a retinoic acid receptor (RAR). RARs belong to the nuclear steroid/thyroid hormone receptor superfamily, and possess a modular structure with discrete ligand binding and DNA binding domains. Of the three isoforms of RARs, RARalpha (RARa) is expressed primarily in hematopoietic cells.
RARa is a member of a family of retinoid-binding transcription factors (including RXR) that regulate gene expression. RARa contains a series of discrete functional domains, including an amino terminal transcriptional activation domain, followed by DNA-binding, dimerization, and retinoid-binding domains. RARa heterodimerizes with retinoid X receptor (RXR), and binds to retinoic acid responsive elements to regulate transcription of target genes .
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- RETINOIC ACID AND THE RETINOIC ACID RECEPTOR
- t(15;17) THE USUAL TRANSLOCATION IN APL
- The PML gene
- The fusion genes of t(15;17)
- - Mechanism of action of PML/RARa
- VARIANT TRANSLOCATIONS
- PLZF/RARa and t(11;17)
- NPM/RARa and t(5;17)
- NuMA/RARa and t(11;17)
- STAT5b/RARa and interstitial chromosome 17 deletion
- BCOR/RARa and t(X;17)(q11;q21.1)
- FLT3 MUTATION