Bailey.Glen: Created page with "==Primary Author(s)*== Yiming Zhong, Ph.D., Megan Piazza, Ph.D., and Shashi Shetty, Ph.D. TOC ==Cancer Category/Type== Acute Myeloid Leukaemia ==Cancer Sub-Classifica..."

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Created page with "==Primary Author(s)*== Yiming Zhong, Ph.D., Megan Piazza, Ph.D., and Shashi Shetty, Ph.D. __TOC__ ==Cancer Category/Type== Acute Myeloid Leukaemia ==Cancer Sub-Classifica..."

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==Primary Author(s)*==

Yiming Zhong, Ph.D., Megan Piazza, Ph.D., and Shashi Shetty, Ph.D.

__TOC__

==Cancer Category/Type==

Acute Myeloid Leukaemia

==Cancer Sub-Classification / Subtype==

Acute Promyelocytic Leukemia (APL) with PML-RARA

==Definition / Description of Disease==

This is a distinct entity in the World Health Organization (WHO) classification system, and associated French-American-British (FAB) classification is acute promyelocytic leukemia (APL, M3)<ref name=":0">Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p134-136.</ref>.

==Synonyms / Terminology==

APL with t(15;17)(q24.1;q21.1)

AML with t(15;17)(q24.1;q21.1)

==Epidemiology / Prevalence==
Accounts for 5-8% of AML, may occur at any age, but predominantly in adult in mid-life<ref name=":0" />.

==Clinical Features==
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" />.

==Sites of Involvement==

Bone marrow

==Morphologic Features==

The abnormal promyelocytes of typical APL have irregular and variable nuclear size and shapes. They are frequently kidney-shaped or bilobed. The cytoplasm is characterized by large granules and stains bright pink, red or purple in Romanowsky staining. In most cases, there are bundles of Auer rods (“faggot cells”) in the cytoplasm. Myeloblasts with single Auer rods may also be present. Auer rods in typical APL are usually larger than those in other types of AML. Microgranular APL is characterized by apparent paucity or absence of granules and predominantly bilobed nuclear shape. The myeloperoxidase (MPO) reaction for both typical and microgranular APL is positive<ref name=":0" />.

==Immunophenotype==

The immunophenotype has been well characterized<ref name=":0" /><ref>{{Cite journal|last=Dong|first=Henry Y.|last2=Kung|first2=Jia Xue|last3=Bhardwaj|first3=Vatsala|last4=McGill|first4=John|date=2011|title=Flow cytometry rapidly identifies all acute promyelocytic leukemias with high specificity independent of underlying cytogenetic abnormalities|url=https://www.ncbi.nlm.nih.gov/pubmed/21173127|journal=American Journal of Clinical Pathology|volume=135|issue=1|pages=76–84|doi=10.1309/AJCPW9TSLQNCZAVT|issn=1943-7722|pmid=21173127}}</ref><ref>{{Cite journal|last=Gorczyca|first=Wojciech|date=2012|title=Acute promyelocytic leukemia: four distinct patterns by flow cytometry immunophenotyping|url=https://www.ncbi.nlm.nih.gov/pubmed/22535601|journal=Polish Journal of Pathology: Official Journal of the Polish Society of Pathologists|volume=63|issue=1|pages=8–17|issn=1233-9687|pmid=22535601}}</ref>.

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||CD13, CD33, CD117, myeloperoxidase (MPO)
|-
|Positive (subset)||CD2 (microgranular APL), CD34 (microgranular APL), CD56 (20% of APL, associated with a worse outcome)
|-
|Negative (universal)||HLA-DR, CD15, CD11a, CD11b, CD11c, CD18
|-
|Negative (subset)||CD2 (typical APL), CD34 (typical APL)
|}

==Chromosomal Rearrangements (Gene Fusions)==
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>.

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|t(15;17)(q24.1;q21.1)||5'PML / 3'RARA||der(15)||5-8% of AML
|}

==Characteristic Chromosomal Aberrations / Patterns==

Not applicable

==Genomic Gain/Loss/LOH==

Not applicable

==Gene Mutations (SNV/INDEL)==
There is not specific information on mutations related to this subtype of AML at this time.
===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||34-45% of APL have FLT3 mutations<ref name=":0" />.
|-
|Secondary Mutations||About 40% of APL cases have secondary cytogenetic abnormalities with trisomy 8 being the most frequent (10-15%)<ref name=":0" />.
|-
|Mutually Exclusive||Not applicable
|}

==Epigenomics (Methylation)==

Not applicable

==Genes and Main Pathways Involved==

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>.

==Diagnostic Testing Methods==

Karyotype, FISH, RT-PCR

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
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>.

==Familial Forms==
Not applicable

==Other Information==
Not applicable

==Links==

[[PML]]

[[RARA]]

==References==
<references />

==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

[[Category:Translocation]]
[[Category:Translocation Chromosome 15]]
[[Category:Translocation Chromosome 17]]
[[Category:Structural Chromosome Abnormalities]]
[[Category:Structural Chromosome Abnormalities in AML]]
[[Category:Structural Abnormalities Chromosome 15]]
[[Category:Structural Abnormalities Chromosome 17]]
[[Category:Fusion Genes in AML]]
[[Category:Fusion Genes P]]
[[Category:Fusion Genes R]]
[[Category:Recently Added Pages]]
[[Category:Cancer Genes P]]
[[Category:Cancer Genes R]]

HAEM4Backup:Acute Promyelocytic Leukemia (APL) with PML-RARA - Revision history

Bailey.Glen: Created page with "==Primary Author(s)*== Yiming Zhong, Ph.D., Megan Piazza, Ph.D., and Shashi Shetty, Ph.D. __TOC__ ==Cancer Category/Type== Acute Myeloid Leukaemia ==Cancer Sub-Classifica..."

Bailey.Glen: Created page with "==Primary Author(s)*== Yiming Zhong, Ph.D., Megan Piazza, Ph.D., and Shashi Shetty, Ph.D. TOC ==Cancer Category/Type== Acute Myeloid Leukaemia ==Cancer Sub-Classifica..."