View source for HAEM4:Acute Myeloid Leukemia (AML) with Recurrent Genetic Abnormalities

==Primary Author(s)*==
Dan Wang, Ph.D.

Daynna J. Wolff, Ph.D.

__TOC__

==General Disease Overview / Description of Cancer Category==
'''Introduction'''

The World Health Organization (WHO) category "AML with recurrent genetic abnormalities" accounts for approximately 20-30% of AML cases<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, Seibert R, Editors. IARC Press: Lyon, France, p130-145.</ref>. The 2016 classification describes nine specific AML subtypes based on structural rearrangements or genetic mutations. There are also two provisional entities: AML with mutated ''RUNX1'' and AML with BCR-ABL1.


'''Acute myeloid leukemia with balanced translocation/inversion'''

The recurrent genetic abnormalities in acute myeloid leukemia (AML) have an important role in predicting remission rate, relapse, treatment selection, and overall survival. The well-characterized balanced translocations/inversions include t(15;17)(q24.1;q21.2), t(8;21)(q22;q22.1), t(9;11)(p21.3;q23.3), and inv(16)(p13.1q22) or t(16;16)(p13.1;q22)<ref>{{Cite journal|last=Mrózek|first=Krzysztof|last2=Radmacher|first2=Michael D.|last3=Bloomfield|first3=Clara D.|last4=Marcucci|first4=Guido|date=2009|title=Molecular signatures in acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/19468266|journal=Current Opinion in Hematology|volume=16|issue=2|pages=64–69|doi=10.1097/MOH.0b013e3283257b42|issn=1531-7048|pmc=4209289|pmid=19468266}}</ref>.  Molecular studies have shown that these structural chromosome rearrangements create a fusion gene(s) encoding a chimeric protein. The altered expression and/or structure of cellular gene products leads to functional activation that may contribute to the initiation or progression of leukemogenesis<ref>{{Cite journal|last=Mitelman|first=Felix|last2=Johansson|first2=Bertil|last3=Mertens|first3=Fredrik|date=2007|title=The impact of translocations and gene fusions on cancer causation|url=https://www.ncbi.nlm.nih.gov/pubmed/17361217|journal=Nature Reviews. Cancer|volume=7|issue=4|pages=233–245|doi=10.1038/nrc2091|issn=1474-175X|pmid=17361217}}</ref>.  Many other structural aberrations have been identified as recurrent in  AML patients, but these entities are not as well characterized<ref>{{Cite journal|last=Walker|first=Alison|last2=Mrózek|first2=Krzysztof|last3=Kohlschmidt|first3=Jessica|last4=Rao|first4=Kathleen W.|last5=Pettenati|first5=Mark J.|last6=Sterling|first6=Lisa J.|last7=Marcucci|first7=Guido|last8=Carroll|first8=Andrew J.|last9=Bloomfield|first9=Clara D.|date=2013|title=New recurrent balanced translocations in acute myeloid leukemia and myelodysplastic syndromes: cancer and leukemia group B 8461|url=https://www.ncbi.nlm.nih.gov/pubmed/23225546|journal=Genes, Chromosomes & Cancer|volume=52|issue=4|pages=385–401|doi=10.1002/gcc.22036|issn=1098-2264|pmc=3874732|pmid=23225546}}</ref>.  AML with t(8;21)(q22;q22.1), t(16;16)(p13.1;q22) or inv(16)(p13.1;q22), and acute promyelocytic leukemia with PML-RARA are considered to be acute leukemia without regard to blast cell count.  It is controversial whether all cases with t(9;11)(p21.3;q23.3), t(6;9)(p23;q34.1), inv(3)(q21.3q26.2), t(3;3)(q21.3;q26.2), or t(1;22)(p13.3;q13.1) as well as AML with the BCR-ABL1 fusion should be categorized as AML when the blast cell count is <20%<ref name=":0" />.

       
'''Acute myeloid leukemia with gene mutations'''

AML has long been associated with chromosomal rearrangements, but now it is understood that genetic mutations also play a prominent role in tumorigenesis. A landmark study published in 2013 by the Cancer Genome Atlas Research Network used the genetic data of 200 cases of ''de novo'' AML to identify 23 genes with a significantly high prevalence of mutations. The current WHO classification incorporates the previous provisional entities of AML with mutated nucleophosmin (''NPM1'') and AML with mutated CCAAT/enhancer binding protein alpha (''CEBPA''), with the clarification that the latter refers only to biallelic ''CEBPA'' mutations. It also introduces two new provisional entities: AML with mutated runt-related transcription factor 1 (''RUNX1'') and AML with a BCR, RhoGEF, and GTPase activating protein (''BCR'')-ABL proto-oncogene 1 (''ABL1'') gene fusion (BCR-ABL1)<ref>{{Cite journal|last=Song|first=Xiaolu|last2=Peng|first2=Ye|last3=Wang|first3=Xiaogang|last4=Chen|first4=Yirui|last5=Jin|first5=Lai|last6=Yang|first6=Tianxin|last7=Qian|first7=Meihua|last8=Ni|first8=Wanmao|last9=Tong|first9=Xiangmin|date=2018|title=Incidence, Survival, and Risk Factors for Adults with Acute Myeloid Leukemia Not Otherwise Specified and Acute Myeloid Leukemia with Recurrent Genetic Abnormalities: Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database, 2001-2013|url=https://www.ncbi.nlm.nih.gov/pubmed/29455198|journal=Acta Haematologica|volume=139|issue=2|pages=115–127|doi=10.1159/000486228|issn=1421-9662|pmid=29455198}}</ref>. Since the publication of the WHO classification, additional novel recurrent gene mutations have been identified. ''DMNT3A'', ''TET2'', ''IDH1/2'', ''ASXL1'', and ''PTPN11'' are among the genes most commonly mutated, some of which are considered initiating or “founder” mutations, whereas others are secondary events involved in disease progression<ref>{{Cite journal|last=Lin|first=Pei|last2=Falini|first2=Brunangelo|date=2015|title=Acute Myeloid Leukemia With Recurrent Genetic Abnormalities Other Than Translocations|url=https://www.ncbi.nlm.nih.gov/pubmed/26071459|journal=American Journal of Clinical Pathology|volume=144|issue=1|pages=19–28|doi=10.1309/AJCP97BJBEVZEUIN|issn=1943-7722|pmid=26071459}}</ref>. In addition, a greater understanding of recurrent mutations in AML has led to the development of a number of targeted therapeutic drugs. Most notably, the identification of ''FLT3'' internal tandem duplications (FLT3-ITD) and tyrosine kinase domain mutations (FLT3-TKD) has facilitated the FDA-approval of the tyrosine kinase inhibitor midostaurin in 2017<ref>{{Cite journal|last=Stone|first=Richard M.|last2=Mandrekar|first2=Sumithra J.|last3=Sanford|first3=Ben L.|last4=Laumann|first4=Kristina|last5=Geyer|first5=Susan|last6=Bloomfield|first6=Clara D.|last7=Thiede|first7=Christian|last8=Prior|first8=Thomas W.|last9=Döhner|first9=Konstanze|date=2017|title=Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation|url=https://www.ncbi.nlm.nih.gov/pubmed/28644114|journal=The New England Journal of Medicine|volume=377|issue=5|pages=454–464|doi=10.1056/NEJMoa1614359|issn=1533-4406|pmc=5754190|pmid=28644114}}</ref>. More recently, a selective inhibitor of mutated ''IDH2'', enasidenib, was approved for the treatment of relapsed or refractory IDH2-mutated AML<ref>{{Cite journal|last=Stein|first=Eytan M.|date=2018|title=Enasidenib, a targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/29243965|journal=Future Oncology (London, England)|volume=14|issue=1|pages=23–40|doi=10.2217/fon-2017-0392|issn=1744-8301|pmid=29243965}}</ref>.

==WHO Classification Pages (Includes Links to Content)==

*[[HAEM5:Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion]]
*[[HAEM5:Acute myeloid leukaemia with CBFB::MYH11 fusion]]
*[[HAEM5:Acute promyelocytic leukaemia with PML::RARA fusion]]
*[[HAEM5:Acute myeloid leukaemia with KMT2A rearrangement]]
*[[HAEM5:Acute myeloid leukaemia with DEK::NUP214 fusion]]
*[[HAEM5:Acute myeloid leukaemia with MECOM rearrangement]]
*[[HAEM5:Acute myeloid leukaemia with RBM15::MRTFA fusion]]
*[[HAEM5:Acute myeloid leukaemia with BCR::ABL1 fusion]]
*[[HAEM5:Acute myeloid leukaemia with NPM1 mutation]]
*[[HAEM5:Acute myeloid leukaemia with CEBPA mutation]]
*[[HAEM4:Acute Myeloid Leukemia (AML) with Mutated RUNX1]]

==Other Related Pages (Includes Links to Content)==

*[[HAEM5:Myeloid/lymphoid neoplasm with FLT3 rearrangement]]

==Additional Information==
NA

==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.

<nowiki>*</nowiki>The hierarchical tumour classification structure displayed on this page is reproduced from the [https://tumourclassification.iarc.who.int/welcome/ WHO Classification of Tumours] with permission from the copyright holder, ©International Agency for Research on Cancer.


[[Category:Structural Abnormalities]]
[[Category:Translocation]]
[[Category:Inversion]]
[[Category:Structural Chromosome Abnormalities in AML]]
[[Category:Fusion Genes in AML]]
[[Category:Oncogenes in AML]]
[[Category:Cancer Genes A]]
[[Category:Cancer Genes B]]
[[Category:Cancer Genes C]]
[[Category:Cancer Genes D]]
[[Category:Cancer Genes F]]
[[Category:Cancer Genes I]]
[[Category:Cancer Genes N]]
[[Category:Cancer Genes P]]
[[Category:Cancer Genes R]]
[[Category:Cancer Genes T]]
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