Acute Promyelocytic Leukemia with t(15;17)(q22;q21), PML-RARA and Variants

Acute Promyelocytic Leukemia with t(15;17)(q22;q21), PML-RARA and Variants

Mohammad A. Vasef, MD

Wright-stained cytospin preparation of a peripheral blood smear of a hypogranular variant-type of acute promyelocytic leukemia demonstrates frequent bilobed blasts and a faggot cell image.

Myeloperoxidase (MPO)-stained peripheral blood smear of a case of hypogranular acute promyelocytic leukemia shows strong MPO positivity despite the submicroscopic nature of the cytoplasmic granules.



  • Acute promyelocytic leukemia (APL)


  • APL with t(15;17)(q22;q21), PML-RARA (current 2008 WHO classification)

  • Acute myeloid leukemia (AML), M3 subtype, FAB classification (AML-M3)


  • Acute promyelocytic leukemia with t(15;17)(q22;q21), PML-RARA

    • Distinct subtype of AML with increased abnormal promyelocytes and blasts

    • Blockage of maturation of granulocytic lineages at promyelocyte stage

    • 15;17 balanced reciprocal translocation represents karyotypic hallmark of disease

  • 3 subtypes of APL

    • Typical APL or hypergranular variant

      • Abnormal promyelocytes with irregular and often bilobed nuclei

      • Numerous large cytoplasmic granules

      • Abnormal cells with numerous Auer rods (faggot cells) can be identified in majority of cases

    • Hypogranular (microgranular) APL variant

      • Frequent marked leukocytosis

      • Absent or scant cytoplasmic granules by light microscopy

      • Presence of abundant submicroscopic granules highlighted by strong myeloperoxidase reactivity

      • Frequent bilobed nuclei (sliding plates)

      • Rare “faggot cells” present in most cases

    • APL variants with non-PML gene rearranged with RARA gene

      • AML with t(5;17)(q35;q21), NPM1-RARA

      • AML with t(11;17)(q23;q21), ZBTB16-RARA

      • AML with t(11;17)(q13;q21), NUMA1-RARA

      • AML with t(17;17)(q11.2;q21), STAT5B-RARA


Molecular Pathogenesis

  • Classic APL is caused by (15:17)(q22;q21) chromosomal translocation

    • t(15;17)(q22;q21) occurs exclusively in APL

    • Retinoic acid receptor alpha (RARA) gene on 17q21 fused with promyelocytic leukemia (PML) gene on 15q22

    • Wild-type PML gene acts as tumor suppressor gene

    • RARA gene promotes cell differentiation and suppresses cell growth

    • Breakpoint in RARA gene consistently occurs in intron 2

    • Breakpoints in PML gene occur in 3 different sites

      • Intron 6 (bcr1), resulting in long form transcript

      • Exon 6 (bcr2), resulting in variable form transcript

      • Intron 3 (bcr3), resulting in short form transcript

    • Novel PML-PARA fusion gene generated on chromosome 15

    • PML-RARA fusion gene encodes PML-RARA fusion protein

  • Functions of novel PML-RARA fusion protein

    • Key role in molecular pathogenesis of APL

    • Disrupts endogenous signaling pathways of both PML and RARA

    • Blocks myeloid differentiation

    • Myeloid differentiation block appears necessary but not sufficient for development of APL

    • Mutations in oncogenes such as FLT3 may cooperate with PML-RARA to induce leukemia

  • APL with cryptic PML-RARA rearrangement

    • Cryptic PML-RARA rearrangements not detectable by conventional cytogenetics

    • FISH using targeted probes usually detects cryptic PML-RARA rearrangements

  • FISH using targeted probes may fail to detect cryptic PML-RARA in rare cases

    • RT-PCR successfully detects and subtypes all 3 forms of PML-RARA transcripts

    • No major biologic differences compared to classic APL with t(15;17)(q22;q21)

  • APL with variant RARA translocations

    • Classified as AML with variant RARA translocations

    • AML with t(5;17)(q35;q21), NPM1-RARA

      • Nucleophosmin (NPM1) gene on 5q35 fused with RARA gene on 17q21

    • AML with t(11;17)(q23;q21), ZBTB16-RARA

      • ZBTB16 (previously PLZF) gene on 11q23 fused with RARA gene on 17q21

    • AML with t(11;17)(q13;q21), NUMA1-RARA

      • NUMA1 (nuclear mitotic apparatus) gene on 11q13 fused with RARA gene on 17q21

    • AML with t(17;17)(q11.2;q21), STAT5B-RARA

      • Signal transducer & activator of transcription STAT5B gene fused with RARA gene



  • Incidence

    • Accounts for 5-8% of AML cases

    • Independent risk factors of APL diagnosis among patients with AML are young age, Hispanic background, and obesity


  • Acute promyelocytic leukemia with t(15;17) (q22;q21), PML-RARA

  • Chief clinical feature in APL is life-threatening coagulopathy and bleeding diathesis due to

    • Plasmin-dependent primary fibrinolysis

    • Disseminated intravascular coagulation (DIC)

  • Marked leukocytosis in hypogranular variant

  • (15;17)(q22;q21) chromosomal translocation is the hallmark of disease


Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Acute Promyelocytic Leukemia with t(15;17)(q22;q21), PML-RARA and Variants
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