HAEM5:Acute myeloid leukaemia with KMT2A rearrangement: Difference between revisions

Patients may present with disseminated intravascular coagulation (DIC), extramedullary myeloid (monocytic) sarcomas, and/or tissue infiltration involving the gingiva and skin<ref name=":0" />.  

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==Sites of Involvement==

This AML subtype is classified based on the translocation between chromosomes 9 and 11, specifically t(9;11)(p21.3;q23.3).  This translocation leads to the fusion of the 5’ portion of ''KMT2A'' at 11q23.3 and the 3’ portion of ''MLLT3'' at 9p21.3.  Both reciprocal fusions are expressed, however, the KMT2A-MLLT3 fusion on the derivative chromosome 11 is the candidate oncoprotein as it contains the putative functional domains of both proteins<ref name=":0" /><ref name=":1" /><ref name=":3">{{Cite journal|last=Mrózek|first=K.|last2=Heinonen|first2=K.|last3=Lawrence|first3=D.|last4=Carroll|first4=A. J.|last5=Koduru|first5=P. R.|last6=Rao|first6=K. W.|last7=Strout|first7=M. P.|last8=Hutchison|first8=R. E.|last9=Moore|first9=J. O.|date=1997|title=Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study|url=https://www.ncbi.nlm.nih.gov/pubmed/9373264|journal=Blood|volume=90|issue=11|pages=4532–4538|issn=0006-4971|pmid=9373264}}</ref>.

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* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

Patients with t(9;11) resulting in a fusion between ''KMT2A'' and ''MLLT3'' and ≥20% blasts are diagnosed with AML with t(9;11).  AML with t(9;11)(p21.3;q23.3) has an intermediate survival, which is superior to AML with other 11q23 translocations<ref name=":3" /><ref>{{Cite journal|last=Rubnitz|first=Jeffrey E.|last2=Raimondi|first2=Susana C.|last3=Tong|first3=Xin|last4=Srivastava|first4=Deo Kumar|last5=Razzouk|first5=Bassem I.|last6=Shurtleff|first6=Sheila A.|last7=Downing|first7=James R.|last8=Pui|first8=Ching-Hon|last9=Ribeiro|first9=Raul C.|date=2002|title=Favorable impact of the t(9;11) in childhood acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/11981001|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=20|issue=9|pages=2302–2309|doi=10.1200/JCO.2002.08.023|issn=0732-183X|pmid=11981001}}</ref>.  There have been over 50 ''KMT2A'' translocation partners identified<ref>{{Cite journal|last=Meyer|first=C.|last2=Schneider|first2=B.|last3=Jakob|first3=S.|last4=Strehl|first4=S.|last5=Attarbaschi|first5=A.|last6=Schnittger|first6=S.|last7=Schoch|first7=C.|last8=Jansen|first8=M. W. J. C.|last9=van Dongen|first9=J. J. M.|date=2006|title=The MLL recombinome of acute leukemias|url=https://www.ncbi.nlm.nih.gov/pubmed/16511515|journal=Leukemia|volume=20|issue=5|pages=777–784|doi=10.1038/sj.leu.2404150|issn=0887-6924|pmid=16511515}}</ref><ref>{{Cite journal|last=Shih|first=L.-Y.|last2=Liang|first2=D.-C.|last3=Fu|first3=J.-F.|last4=Wu|first4=J.-H.|last5=Wang|first5=P.-N.|last6=Lin|first6=T.-L.|last7=Dunn|first7=P.|last8=Kuo|first8=M.-C.|last9=Tang|first9=T.-C.|date=2006|title=Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement|url=https://www.ncbi.nlm.nih.gov/pubmed/16341046|journal=Leukemia|volume=20|issue=2|pages=218–223|doi=10.1038/sj.leu.2404024|issn=0887-6924|pmid=16341046}}</ref> and one of the most common partners is ''MLLT3''<ref name=":0" />.  

Patients presenting with t(9;11)(p22;q23) and <20% blasts should be monitored closely for more definite evidence of AML.

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

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The t(9;11)( p21.3;q23.3) can present with secondary abnormalities, most frequently trisomy of chromosome 8<ref name=":1" /><ref name=":3" />.

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==Characteristic Chromosomal Patterns==

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Not applicable

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==Gene Mutations (SNV / INDEL)==

NA

NA

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==Epigenomic Alterations==

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The ''KMT2A'' (Lysine Methyltransferase 2A) gene encodes a protein that complexes with other proteins and functions to regulate gene transcription through chromatin remodeling.  This protein plays a vital role in regulating gene expressing during early development and hematopoiesis.  The ''MLLT3'' (Super Elongation Complex Subunit) gene encodes a protein that is an element of the super elongation complex (SEC).  The SEC is a complex that plays an essential role in regulating the activity of RNA polymerase II transcription.  The fusion protein created, KMT2A-MLLT3, leads to the promotion of transcriptional elongation, activation of genes that would typically be silenced, and thus inhibits hematopoietic cells from properly maturing<ref>{{Cite journal|last=Mueller|first=Dorothee|last2=García-Cuéllar|first2=María-Paz|last3=Bach|first3=Christian|last4=Buhl|first4=Sebastian|last5=Maethner|first5=Emanuel|last6=Slany|first6=Robert K.|date=2009|title=Misguided transcriptional elongation causes mixed lineage leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/19956800|journal=PLoS biology|volume=7|issue=11|pages=e1000249|doi=10.1371/journal.pbio.1000249|issn=1545-7885|pmc=2774266|pmid=19956800}}</ref>.

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==Genetic Diagnostic Testing Methods==