Acute Promyelocytic Leukemia: A Review and Discussion of Variant Translocations

Abstract

The majority of patients with acute promyelocytic leukemia (APL) manifest the t(15;17)(q24.1;q21.2) translocation; however, a minor but significant proportion of patients with APL harbor complex, cryptic, or variant translocations, which typically involve RARA. With the exception of ZBTB16/RARA, these variants have similar morphologic and immunophenotypic features as classic APL. Study of the variant forms of APL not only gives insight into the pathogenesis of APL but also allows us to understand the mechanism of retinoid therapy. It is important to identify these cryptic and variant translocations because certain variants, including ZBTB16/RARA and STAT5B/RARA, are resistant to treatment with all-trans retinoic acid, arsenic trioxide, and anthracyclines. A cute promyelocytic leukemia (APL), comprising 5% to 8% of cases of acute myeloid leukemia (AML), is one of the best studied and understood hematopoietic malignancies. Unlike other forms of AML, APL is unique in that it can cause coagulopathy and death if not readily diagnosed.1,2 Morphologically classified as AML-M3 by the French-American-British (FAB) classification, APL is typically characterized by neoplastic proliferation of cells in the bone marrow with a promyelocytic phenotype and the balanced reciprocal translocation t(15;17) (q24.1;q21.2), which results in the expression of the promyelocytic leukemia (PML)-retinoic acid receptor-a (RARA) fusion protein.

Study of the mechanisms of crocetin‐induced differentiation and apoptosis in human acute promyelocytic leukemia cells

“…Cytogenetically, it is characterized by chromosomal translocation t(15;17)(q22;q21) in the majority of patients. This translocation leads to the fusion between the retinoic acid receptor‐α (RARα) and promyelocytic leukemia (PML) genes . Both RARα and PML play key roles in hematopoiesis, and the gain‐of‐function PML‐RARα fusion protein prevents the antiproliferative and proapoptotic effects of PML.…”

“…Both RARα and PML play key roles in hematopoiesis, and the gain‐of‐function PML‐RARα fusion protein prevents the antiproliferative and proapoptotic effects of PML. This fusion also recruits histone deacetylases (HDACs) resulting in the repression of the differentiating role of retinoic acid . Therefore, HDAC inhibitors are suggested as valuable therapeutic agents for this form of leukemia …”

Molecular Profiling: A Case ofZBTB16-RARAAcute Promyelocytic Leukemia

“…Retinoid-based therapy in combination with either anthracyclines or arsenic trioxide results in favorable rates of complete remission and overall survival, provided that the patient can be supportively managed through the initial coagulopathy [1]. However, a small proportion of patients harbor variant translocations that result in fusion of RARA to one of a number of alternative partner genes [2, 3]. The most often reported of these variant translocations is the t(11;17)(q23;q21) which results in the fusion of the zinc finger gene ZBTB16 (formerly PLZF ) to the RARA locus [4, 5].…”

A Paediatric Acute Promyelocytic Leukaemia Patient Harbouring a Cryptic <b><i>PML-RARA</i></b> Insertion due to a Complex Structural Chromosome 17 Rearrangement

“…Among all these variant forms, RARA is consistently involved supporting its role in APL pathogenesis, which has been implicated in regulation of development, differentiation, apoptosis, and granulopoiesis. Variant translocations involving PML have not been described [Adams and Nassiri, 2015].…”

“…Rapid diagnosis of APL is important due to the high risk of disseminated intravascular coagulation leading to internal bleeding and death [Adams and Nassiri, 2015]. Immediate treatment with both all-trans retinoic acid (ATRA) [Huang et al, 1988] and arsenic trioxide (ATO) has proven to be very effective in obtaining high clinical complete remission rates ( ≥ 90%) and disease-free survival in adult APL, especially if consolidated with anthracycline [Shen et al, 2004;Long et al, 2014].…”