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

{{DISPLAYTITLE:Acute promyelocytic leukaemia with PML::RARA fusion}}

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==Primary Author(s)*==

==Clinical Features==

{| class="wikitable"

|'''Signs and Symptoms'''

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|'''Laboratory Findings'''

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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" />.

!Notes

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|Yes

|No

|Yes

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

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>.  

* Chromosomal Rearrangements (Gene Fusions)

* Individual Region Genomic Gain/Loss/LOH

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

{| class="wikitable sortable"

!Notes

|-

7

chr7:1- 159,335,973 [hg38]

chr7

|Yes

|No

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

|-

8

chr8:1-145,138,636 [hg38]

chr8

|No

|No

Common recurrent secondary finding for t(8;21) (add reference).

|}

Not applicable

==Characteristic Chromosomal Patterns==

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!Notes

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Co-deletion of 1p and 18q

|No

|No

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

|}

Not applicable

==Gene Mutations (SNV / INDEL)==

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!Notes

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EGFR; Exon 20 mutations

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|

|

<br />

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

===Other Mutations===

==Genes and Main Pathways Involved==

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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

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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>.