View source for HAEM4Backup:Mixed Phenotype Acute Leukemia (MPAL) with t(v;11q23.3); KMT2A Rearranged

==Primary Author(s)*==

Tracy Tucker, PhD, FCCMG

__TOC__

==Cancer Category/Type==

[[AML|Acute Myeloid Leukemia]]

[[Acute Leukemias of Ambiguous Lineage]]

==Cancer Sub-Classification / Subtype==

Mixed-phenotype acute leukemia with t(v;11q23.3); KMT2A-rearranged

==Definition / Description of Disease==

Mixed-phenotype acute leukemia (MPAL) with t(v;11q23.3) results in ''KMT2A'' rearrangement with a number of different fusion partners and defines a subtype of MPAL, which are leukemias in which the blast cells show no clear differentiation along a single lineage and instead have both myeloid and lymphoid immunophenotypic markers<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>. 

•	''KMT2A'' is commonly rearranged with 4q21.2 (''AFF1''), although other loci have been reported including 9p21, 9p22,10p12 and 19p13<ref name=":0">{{Cite journal|last=Manola|first=Kalliopi N.|date=2013|title=Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview|url=https://www.ncbi.nlm.nih.gov/pubmed/23888868|journal=British Journal of Haematology|volume=163|issue=1|pages=24–39|doi=10.1111/bjh.12484|issn=1365-2141|pmid=23888868}}</ref><ref name=":1">{{Cite journal|last=Yan|first=Lingzhi|last2=Ping|first2=Nana|last3=Zhu|first3=Mingqing|last4=Sun|first4=Aining|last5=Xue|first5=Yongquan|last6=Ruan|first6=Changgeng|last7=Drexler|first7=Hans G.|last8=Macleod|first8=Roderick A. F.|last9=Wu|first9=Depei|date=2012|title=Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification|url=https://www.ncbi.nlm.nih.gov/pubmed/22581002|journal=Haematologica|volume=97|issue=11|pages=1708–1712|doi=10.3324/haematol.2012.064485|issn=1592-8721|pmc=3487445|pmid=22581002}}</ref>.

==Synonyms / Terminology==

Mixed-phenotype acute leukemia with t(v;11q23); MLL rearranged

Mixed phenotype acute leukemia with MLL rearranged

==Epidemiology / Prevalence==

MPAL accounts for 2-5% of all acute leukemias<ref name=":0" />, and the t(v;11q23) is one of two genetically defined entities in MPAL.  MPAL with t(v;11q23) has been reported in both the adult and pediatric population<ref name=":0" /><ref name=":1" />.

==Clinical Features==

MPAL with t(v;11q23) patients have a similar presentation to other patients with acute leukemia, and likely present similarly to patients with other acute leukemias with ''KMT2A'' rearrangement that have a high white blood cell count.

==Sites of Involvement==

Bone marrow

==Morphologic Features==

•	Blasts must constitute 20% of all nucleated cells, but not necessarily of each distinct lineage.

•	Blasts are dimorphic  -  resembling both lymphoblasts and myeloblasts.

==Immunophenotype==
The diagnosis of MPAL rests on the immunophenotypic features of blasts rather than morphology and flow cytometry. 

The following are criteria for assigning more than one lineage to a single blast population: 

•	 Myeloid lineage – MPO by flow cytometry, immunohistochemistry, or cytochemistry OR monocytic differentiation with two of the following: non-specific esterase, CD11c, CD14, CD64, lysozyme

•	T-cell lineage – cytoplasmic or surface CD3 expression

•	B-cell lineage – strong CD19 with one of the following strongly expressed: CD79a, cytoplasmic CD22, CD10 OR weak CD19 with two of the following strongly expressed:CD79a, cytoplasmic CD22, CD10

==Chromosomal Rearrangements (Gene Fusions)==

Almost all cases have a t(v;11q23) identified by karyotype analysis or a ''KMT2A'' break-apart by FISH analysis. 

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|t(4;11)(q21;q23)||3'AFF1 / 5'KMT2A||der(11)||Most common
|-
|t(9;11)(p22;q23)||3’MLLT3 / 5’KMT2A||der(11)||
|-
|t(10;11)(p12;q23)||3’MLLT10 / 5’KMT2A||der(11)||
|-
|t(11;19)(q23;p13.3)||3’MLLT1 / 5’KMT2A||der(11)||
|}

==Characteristic Chromosomal Aberrations / Patterns==

May exist as the sole abnormality or with secondary abnormalities.  Given the rarity of cases, common secondary abnormalities have not been identified.

==Genomic Gain/Loss/LOH==

Not known in this specific subgroup.

==Gene Mutations (SNV/INDEL)==

Not known in this specific subgroup.

==Epigenomics (Methylation)==

Not known in this specific subgroup.

==Genes and Main Pathways Involved==

Genes:

•	''KMT2A'' on 11q23.3 is transcribed from centromere to telomere.  It encodes a transcriptional coactivator with two DNA binding motifs (an AT hook, and Zinc fingers), a DNA methyl transferase motif (SET domain), a bromodomain; transcriptional regulatory factor and nuclear localization. When ''KMT2A'' is part of a multiprotein complex, the SET domain specifically mediates methylation of Lys-4 of histone H3 (H3K4me) which is a tag for epigenetic activation and mediates acetylation of Lys-16 of histone H4 (H4K16ac). 

•	''AFF1'' on 4q21.3 is transcribed from centromere to telomere.  It encodes a transcription factor that regulates RNA polymerase II-mediated transcription through elongation and chromatin remodeling functions. This gene has been shown to promote the expression of CD133, a plasma membrane glycoprotein required for leukemia cell survival. 

•	''MLLT3'' on 9p21.3 is transcribed from centromere to telomere. It encodes for a transcription factor that is part of the super-elongation complex (SEC) that increases the catalytic rate of RNA polymerase II transcription by suppressing polymerase pausing. 

•	''MLLT10'' on 10p12.31 is transcribed from telomere to centromere.  It encodes a transcription factor with both zinc finger and leucine zipper motifs.  

•	''MLLT1'' on 19p13.3 is transcribed from centromere to telomere. It encodes for a transcription factor that is part of the super-elongation complex (SEC) that increases the catalytic rate of RNA polymerase II transcription by suppressing polymerase pausing.


DNA:

•	5' ''KMT2A'' - 3' ''AFF1'' has variable breakpoints.
 
•	5' ''KMT2A'' - 3' ''MLLT3'' has variable breakpoints.

•	5' ''KMT2A'' - 3' ''MLLT10'' has variable breakpoints, however, given that ''MLLT10'' is transcribed in the opposite direction to ''KMT2A'', most result from a complex rearrangement. 

•	5' ''KMT2A'' - 3' ''MLLT1'' has variable breakpoints. 	 


Protein:

•	5' KMT2A - 3' AFF1 fusion product consists of the AT hook and DNA methyltransferase from KMT2A fused to the AFF1 C-terminus on the derivative 11 and is predominantly located in the nucleus.  The reciprocal AFF1-KMT2A on the derivative 4 may or may not be expressed. 

•	 5' KMT2A- 3' MLLT3 fusion product consists of the AT hook and DNA methyltransferase from KMT2A fused to the MLLT3 C-terminus on the derivative 11 and is predominantly located in the nucleus.

•	 5' KMT2A - 3' MLLT10 fusion product consists of the AT hook and DNA methyltransferase from KMT2A fused to the MLLT10 leucine zipper on the derivative 11 and is predominantly located in the nucleus. 

•	5' KMT2A - 3' MLLT1 fusion product consists of the AT hook and DNA methyltransferase from KMT2A fused to most of the MLLT1 gene. 

	
Key cellular pathways: 

•	The partners listed above are all transcriptional regulators that are widely expressed.  Regardless of the partner, the methyltransferase activity is lost in the ''KMT2A'' fusion product. Although the exact mechanism has not been fully elucidated, the loss of methyltransferase activity results in epigenetic changes in the genome<ref>Johansson B and Harrison CJ (2009). Cancer Cytogenetics: Chromosomal and Molecular Genetic Aberrations of Tumor Cells, 3<sup>rd</sup> edition. Heim S, Mitelman F, Editors. John Wiley & Sons Inc: Hoboken, New Jersey, p84-87.</ref>.

==Diagnostic Testing Methods==

•	Chromosome analysis, FISH

•	FISH is needed for cytogenetically cryptic cases with typical immunophenotype

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
Diagnostic:

•	The presence of t(v;11q23) with mixed phenotype immune-profile is diagnostic of this cytogenetic subtype of MPAL. 


Prognostic:

•	t(v;11q23) MPAL has a poor prognosis, similar to other most other leukemias with ''KMT2A'' rearrangements. 


Therapeutic target:

•	No specific molecular targets

==Familial Forms==

None

==Other Information==

None

==Links==

[[KMT2A]]

==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 11]]
[[Category:Structural Chromosome Abnormalities]]
[[Category:Structural Chromosome Abnormalities in AML]]
[[Category:Structural Abnormalities Chromosome 11]]
[[Category:Fusion Genes in AML]]
[[Category:Cancer Genes K]]
[[Category:Cancer Genes M]]
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