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.


TERMINOLOGY


Abbreviations



  • Acute promyelocytic leukemia (APL)


Synonyms



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


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


Definitions



  • 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


ETIOLOGY/PATHOGENESIS


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


CLINICAL ISSUES


Epidemiology



  • 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


Presentation



  • 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


Treatment

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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