What is the pathophysiology of acute promyelocytic leukemia (APL)?

Updated: May 03, 2019
  • Author: Sandy D Kotiah, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

Acute promyelocytic leukemia (APL) is defined by its cytogenetic properties. Over 95% of cases are characterized by a balanced translocation between chromosome 17q21 and chromosome 15q22. This leads to an abnormal fusion protein called PML-RARA. This translocation can be detected by karyotyping or fluorescence in situ hybridization (FISH) studies, and the transcript can be detected by polymerase chain reaction (PCR) techniques.

The retinoic acid alpha receptor gene (RARA) is encoded by the long arm of chromosome 17. It is mainly expressed in hematopoietic cells and has an important role in regulating gene expression. In the absence of retinoid acid, RARA is bound by nuclear corepressor factor, and this causes transcriptional repression. In the presence of retinoic acid, RARA is activated and terminal differentiation of promyelocytes occurs.

The promyelocytic gene (PML) is encoded by the long arm of chromosome 15 and is expressed ubiquitously. PML is thought to be involved in apoptosis and tumor suppression.

There are three possible isoforms caused by PML-RARA translocations. The breakpoint in chromosome 17 is consistently found in intron 2, but varies in chromosome 15. The three breakpoints on the PML gene can occur at intron 3 (L form), intron 6 (S form), and exon 6 (V form). The S form is reportedly associated with a shorter remission duration and overall survival compared with the L form. [3]

The fusion gene product causes the retinoic acid receptor to bind more tightly to the nuclear co-repressor factor. Therefore, the gene cannot be activated with physiologic doses of retinoic acid. In about 5% of cases, rearrangements of chromosome 17q21 with other gene partners occur. These include the following:

  • PZLF (promyelocytic zinc finger) t(11;17)(q23;q21)

  • NPM (nucleophosmin) t(5;17)(q35;q12-21)

  • NuMa (nuclear mitotic apparatus) t(11;17)(q13;q21)

  • STAT5b (17;17)(q11;q21)

Yin et al identified a novel fusion between RARA and the interferon regulatory factor 2 binding protein 2 (IRF2BP2) genes. [4] Cao et al reported on a new karyotype: 46,XY; t(7;16)(q31'q22), t(15;17)(q22;q21). [5]

It is important to note that the nature of the fusion partner significantly impacts the disease characteristics and response to therapy. For example, APL with PLZF-RARA is not sensitive to retinoic acid and is less sensitive to chemotherapy. [6]

About 40% of APL cases also express additional chromosomal abnormalities (trisomy 8 and isochromosome 17). These do not appear to impact the overall prognosis.


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