Molecular Genetics of Acute Promyelocytic Leukaemia


Acute promyelocytic leukaemia (APL) is a rare form of acute myeloid leukaemia (AML) and is the first example of haematological malignancy cured by targeted therapy, commonly based on all‐trans retinoic acid (ATRA) and arsenic trioxide (ATO). APL is the result of a cytogenetic translocation t(15;17)(q24;q21), which creates a functional gene derived from the fusion of the promyelocytic leukaemia (PML) gene with retinoic acid receptor alpha (RARA). The PML/RARA protein acts mainly as a transcription factor able to modify the expression of several genes, such as transcription or epigenetic factors. This accounts for a differentiation block at the promyelocytic stage and a resistance to apoptosis/senescence pathways. A few additional secondary genetic events, including chromosomal and genetic alterations, are required to ultimately trigger the leukaemic phenotype. These alterations are varied; involve recurrent pathways and more than one hundred genes. However, the clinical significance of most of them is still unclear.

Key Concepts

  • Acute promyelocytic leukaemia is the first example of a malignancy cured by targeted therapy.
  • The balanced reciprocal translocation t(15;17)(q24;q21), leading to the PML/RARA fusion gene, is the cytogenetic marker of APL.
  • The expression of PML/RARA protein accounts for a differentiation block at the promyelocytic stage and a resistance to apoptosis/senescence pathways.
  • The two drugs used in clinical practice, all‐trans retinoic acid (ATRA) and arsenic trioxide (ATO), degrade the PML/RARA fusion by acting on the RARA and PML moieties, respectively.
  • Secondary cooperating events to PML/RARA fusion are required to trigger the APL phenotype, including cryptic abnormalities in karyotype and activating mutations.
  • A few acquired nonrecurrent cytogenetic submicroscopic variations have been identified in APL patients and they have a negative impact on the outcomes.
  • A few cooperative but extremely varied mutational events might be required for the establishment of the APL phenotype.
  • Somatic mutations affect similar pathways but not the same genes, suggesting comparable impact on leukaemogenesis.

Keywords: acute promyelocytic leukaemia; cytogenetics; genetics; epigenetics; PML; RARA; translocation; mutations; leukaemia; haematology

Figure 1. The PML/RARA fusion and functions: The t(15;17) translocation produces the PML/RARA fusion gene. This is translated in a functional protein that keeps most of the structural domains of PML (RING‐finger and coiled‐coil domains) and of RARA (DNA‐ and ligand‐binding domains). Owing to this fusion, the PML/RARA interacts with PML through the PML moiety, resulting in the disruption of PML nuclear bodies (NB). Likewise, this fusion induces the creation of heterodimers between PML/RARA and RXR, leading to a change in the recognition of RARA target genes. The two drugs used in clinical practice, all‐trans retinoic acid (ATRA) and arsenic trioxide (ATO), degrade the PML/RARA fusion by acting on the RARA and PML moieties, respectively. As a consequence, NB structures, as well as the transcriptional regulation of RARA target genes, are restored. RBCC: RING‐B‐box‐coiled‐coil (RBCC) domain. NLS: nuclear localisation signal. SIM: SUMO‐interacting motif. NES: Nuclear export signal. AF: activation function domain. DNA‐BD: DNA‐binding domain. Ligand‐BD: ligand‐binding domain. RD: regulatory domains.


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Further Reading

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Liquori, Alessandro, Ibáñez, Mariam, Sanz, Miguel Ángel, Barragán, Eva, and Cervera, José(Jun 2019) Molecular Genetics of Acute Promyelocytic Leukaemia. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028438]