HAEM5:Acute promyelocytic leukaemia with PML::RARA fusion: Difference between revisions

Typical (hypergranular) and microgranular (hypogranular) APL are frequently associated with disseminated intravascular coagulation (DIC).  In contrast to typical APL, microgranular APL is associated with increased counts of leukocytes which have rapid doubling time<ref name=":0" />.

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==Sites of Involvement==

This AML subtype is classified based on the presence of a PML-RARA fusion, which results from fusion of the 5’ portion of PML at 15q24.1 and the 3’ portion of RARA at 17q21.1<ref>{{Cite journal|last=de Thé|first=H.|last2=Chomienne|first2=C.|last3=Lanotte|first3=M.|last4=Degos|first4=L.|last5=Dejean|first5=A.|date=1990|title=The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus|url=https://www.ncbi.nlm.nih.gov/pubmed/2170850|journal=Nature|volume=347|issue=6293|pages=558–561|doi=10.1038/347558a0|issn=0028-0836|pmid=2170850}}</ref>. 5'PML-3'RARA transcript is expressed in all cases, and 5'RARA-3'PML transcript is found in 2/3 of cases<ref>{{Cite journal|last=Warrell|first=R. P.|last2=de Thé|first2=H.|last3=Wang|first3=Z. Y.|last4=Degos|first4=L.|date=1993|title=Acute promyelocytic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/8515790|journal=The New England Journal of Medicine|volume=329|issue=3|pages=177–189|doi=10.1056/NEJM199307153290307|issn=0028-4793|pmid=8515790}}</ref>. Rare cases of APL have cryptic t(15;17)(q24.1;q21.1) such as submicroscopic insertion of RARA into PML leading to the expression of the PML-RARA transcript or three way translocations involving chromosomes 15 and 17 with an additional chromosome<ref name=":1">{{Cite journal|last=Grimwade|first=D.|last2=Gorman|first2=P.|last3=Duprez|first3=E.|last4=Howe|first4=K.|last5=Langabeer|first5=S.|last6=Oliver|first6=F.|last7=Walker|first7=H.|last8=Culligan|first8=D.|last9=Waters|first9=J.|date=1997|title=Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/9389704|journal=Blood|volume=90|issue=12|pages=4876–4885|issn=0006-4971|pmid=9389704}}</ref>.  Several variant translocations involving RARA have also been identified, including t(11;17) and t(5;17)<ref name=":1" />. The 4th edition revision to the World Health Organization renamed APL with t(15;17)(q24.1;q21.1) as APL with PML-RARA<ref name=":0" /><ref>{{Cite journal|last=Arber|first=Daniel A.|last2=Orazi|first2=Attilio|last3=Hasserjian|first3=Robert|last4=Thiele|first4=Jürgen|last5=Borowitz|first5=Michael J.|last6=Le Beau|first6=Michelle M.|last7=Bloomfield|first7=Clara D.|last8=Cazzola|first8=Mario|last9=Vardiman|first9=James W.|date=2016|title=The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/27069254|journal=Blood|volume=127|issue=20|pages=2391–2405|doi=10.1182/blood-2016-03-643544|issn=1528-0020|pmid=27069254}}</ref>.  

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* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

APL can be differentiated from other types of AML based on microscopic examination of the blood, bone marrow, or biopsy as well as detection of the PML/RARA fusion gene. The prognosis in APL treated with all-trans retinoic acid (ATRA) and arsenic trioxide is favorable, and relapsed or refractory APL cases show a generally good response with arsenic trioxide therapy<ref>{{Cite journal|date=2016|title=Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72(2):567-572|url=https://www.ncbi.nlm.nih.gov/pubmed/28034863|journal=Blood|volume=128|issue=26|pages=3017|doi=10.1182/blood-2016-11-750182|issn=1528-0020|pmid=28034863}}</ref><ref>{{Cite journal|last=de Thé|first=Hugues|last2=Pandolfi|first2=Pier Paolo|last3=Chen|first3=Zhu|date=2017|title=Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure|url=https://www.ncbi.nlm.nih.gov/pubmed/29136503|journal=Cancer Cell|volume=32|issue=5|pages=552–560|doi=10.1016/j.ccell.2017.10.002|issn=1878-3686|pmid=29136503}}</ref>. Expression of CD56 is associated with poor prognosis, while the prognostic significance of FLT3 -ITD mutations remains unclear<ref>{{Cite journal|last=Ferrara|first=F.|last2=Morabito|first2=F.|last3=Martino|first3=B.|last4=Specchia|first4=G.|last5=Liso|first5=V.|last6=Nobile|first6=F.|last7=Boccuni|first7=P.|last8=Di Noto|first8=R.|last9=Pane|first9=F.|date=2000|title=CD56 expression is an indicator of poor clinical outcome in patients with acute promyelocytic leukemia treated with simultaneous all-trans-retinoic acid and chemotherapy|url=https://www.ncbi.nlm.nih.gov/pubmed/10715300|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=18|issue=6|pages=1295–1300|doi=10.1200/JCO.2000.18.6.1295|issn=0732-183X|pmid=10715300}}</ref><ref>{{Cite journal|last=Schnittger|first=Susanne|last2=Bacher|first2=Ulrike|last3=Haferlach|first3=Claudia|last4=Kern|first4=Wolfgang|last5=Alpermann|first5=Tamara|last6=Haferlach|first6=Torsten|date=2011|title=Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA|url=https://www.ncbi.nlm.nih.gov/pubmed/21859732|journal=Haematologica|volume=96|issue=12|pages=1799–1807|doi=10.3324/haematol.2011.049007|issn=1592-8721|pmc=3232262|pmid=21859732}}</ref>.

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==Individual Region Genomic Gain / Loss / LOH==

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Not applicable

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==Characteristic Chromosomal Patterns==

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Not applicable

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==Gene Mutations (SNV / INDEL)==

There is not specific information on mutations related to this subtype of AML at this time.

===Other Mutations===

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==Epigenomic Alterations==

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The protein encoded by the PML (promyelocytic leukemia) gene is a member of the tripartite motif (TRIM) family and it functions as a transcription factor and tumor suppressor.  PML is the core component of subnuclear structures called PML nuclear bodies (PML-NBs) and it interacts with a large number of proteins including p53 and has been implicated in several cellular functions such as cellular senescence, apoptosis, and hematopoietic stem cell maintenance<ref>{{Cite journal|last=Pearson|first=M.|last2=Carbone|first2=R.|last3=Sebastiani|first3=C.|last4=Cioce|first4=M.|last5=Fagioli|first5=M.|last6=Saito|first6=S.|last7=Higashimoto|first7=Y.|last8=Appella|first8=E.|last9=Minucci|first9=S.|date=2000|title=PML regulates p53 acetylation and premature senescence induced by oncogenic Ras|url=https://www.ncbi.nlm.nih.gov/pubmed/10910364|journal=Nature|volume=406|issue=6792|pages=207–210|doi=10.1038/35018127|issn=0028-0836|pmid=10910364}}</ref><ref>{{Cite journal|last=Bernardi|first=Rosa|last2=Pandolfi|first2=Pier Paolo|date=2007|title=Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies|url=https://www.ncbi.nlm.nih.gov/pubmed/17928811|journal=Nature Reviews. Molecular Cell Biology|volume=8|issue=12|pages=1006–1016|doi=10.1038/nrm2277|issn=1471-0080|pmid=17928811}}</ref>. The gene RARA (Retinoic acid receptor, alpha) encodes a nuclear retinoic acid receptor which regulates transcription in a ligand-dependent manner<ref>{{Cite journal|last=Melnick|first=A.|last2=Licht|first2=J. D.|date=1999|title=Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/10233871|journal=Blood|volume=93|issue=10|pages=3167–3215|issn=0006-4971|pmid=10233871}}</ref>. The fusion of PML and RARA results in expression of a hybrid protein with altered functions. This fusion protein deregulates transcriptional control such as RAR targets and disrupts PML nuclear bodies<ref>{{Cite journal|last=de Thé|first=Hugues|last2=Chen|first2=Zhu|date=2010|title=Acute promyelocytic leukaemia: novel insights into the mechanisms of cure|url=https://www.ncbi.nlm.nih.gov/pubmed/20966922|journal=Nature Reviews. Cancer|volume=10|issue=11|pages=775–783|doi=10.1038/nrc2943|issn=1474-1768|pmid=20966922}}</ref>.

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==Genetic Diagnostic Testing Methods==