View source for HAEM5:Acute myeloid leukaemia with KMT2A rearrangement

{{DISPLAYTITLE:Acute myeloid leukaemia with KMT2A rearrangement}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]

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<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Acute Myeloid Leukemia (AML) with t(9;11)(p21.3;q23.3); KMT2A-MLLT3]].
}}</blockquote>

<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>

==Primary Author(s)*==

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

__TOC__

==Cancer Category / Type==
Acute Myeloid Leukemia

==Cancer Sub-Classification / Subtype==

Acute myeloid leukemia with t(9;11)(p21.3;q23.3) resulting in KMT2A(MLL)-MLLT3(AF9) fusion

==Definition / Description of Disease==

This is a distinct entity in the World Health Organization (WHO) classification system<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, 136-138.</ref><ref>{{Cite journal|date=2016|title=Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405|url=https://www.ncbi.nlm.nih.gov/pubmed/31659364|journal=Blood|volume=128|issue=3|pages=462–463|doi=10.1182/blood-2016-06-721662|issn=1528-0020|pmid=31659364}}</ref>. 

==Synonyms / Terminology==

AF9/MLL

==Epidemiology / Prevalence==

Accounts for 9-12% of pediatric cases of AML and 1- 2% of adult AML cases<ref name=":1">{{Cite journal|last=Byrd|first=John C.|last2=Mrózek|first2=Krzysztof|last3=Dodge|first3=Richard K.|last4=Carroll|first4=Andrew J.|last5=Edwards|first5=Colin G.|last6=Arthur|first6=Diane C.|last7=Pettenati|first7=Mark J.|last8=Patil|first8=Shivanand R.|last9=Rao|first9=Kathleen W.|date=2002|title=Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461)|url=https://www.ncbi.nlm.nih.gov/pubmed/12393746|journal=Blood|volume=100|issue=13|pages=4325–4336|doi=10.1182/blood-2002-03-0772|issn=0006-4971|pmid=12393746}}</ref><ref>{{Cite journal|last=Forestier|first=Erik|last2=Heim|first2=Sverre|last3=Blennow|first3=Elisabeth|last4=Borgström|first4=Georg|last5=Holmgren|first5=Gösta|last6=Heinonen|first6=Kristiina|last7=Johannsson|first7=Johann|last8=Kerndrup|first8=Gitte|last9=Andersen|first9=Mette Klarskov|date=2003|title=Cytogenetic abnormalities in childhood acute myeloid leukaemia: a Nordic series comprising all children enrolled in the NOPHO-93-AML trial between 1993 and 2001|url=https://www.ncbi.nlm.nih.gov/pubmed/12752097|journal=British Journal of Haematology|volume=121|issue=4|pages=566–577|doi=10.1046/j.1365-2141.2003.04349.x|issn=0007-1048|pmid=12752097}}</ref>.  No gender bias noted.

==Clinical Features==

Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
|'''Signs and Symptoms'''
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)

EXAMPLE B-symptoms (weight loss, fever, night sweats)

EXAMPLE Fatigue

EXAMPLE Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|EXAMPLE Cytopenias

EXAMPLE Lymphocytosis (low level)
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}

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

</blockquote>
==Sites of Involvement==

Bone marrow 

==Morphologic Features==

This subtype may be seen in AML with or without maturation and has a strong association with acute monocytic and myelomonocytic leukemias<ref name=":0" />.  The blasts present are typically monoblasts or promonocytes<ref name=":0" />.  The monoblasts are large cells that have abundant cytoplasm, which may be moderate to intensely basophilic.  The cytoplasm may also show pseudopod formation, scattered and fine azurophilic granules, and vacuoles.  The nuclei of the monoblasts are typically round with delicate lacy chromatin and may contain one or more prominent nucleoli.  The promonocytes have cytoplasm that is less basophilic and may be more granulated, in addition to the presence of the occasional large azurophilic granules and vacuoles.  Mostly these monoblasts and promonocytes are MPO negative by immunohistochemistry.  These cells have a more irregularly shaped and delicately convoluted nuclear configuration. 

==Immunophenotype==

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||CD33, CD65, CD4, and HLA-DR (children); CD14, CD4, CD11b, CD11c, CD64, CD36, and Lysozyme (adults)<ref name=":2">{{Cite journal|last=Muñoz|first=L.|last2=Nomdedéu|first2=J. F.|last3=Villamor|first3=N.|last4=Guardia|first4=R.|last5=Colomer|first5=D.|last6=Ribera|first6=J. M.|last7=Torres|first7=J. P.|last8=Berlanga|first8=J. J.|last9=Fernández|first9=C.|date=2003|title=Acute myeloid leukemia with MLL rearrangements: clinicobiological features, prognostic impact and value of flow cytometry in the detection of residual leukemic cells|url=https://www.ncbi.nlm.nih.gov/pubmed/12529663|journal=Leukemia|volume=17|issue=1|pages=76–82|doi=10.1038/sj.leu.2402708|issn=0887-6924|pmid=12529663}}</ref>
|-
|Positive (subset)||Neuron-glial antigen 2 (NG2) (children and adults)<ref>{{Cite journal|last=Wuchter|first=C.|last2=Harbott|first2=J.|last3=Schoch|first3=C.|last4=Schnittger|first4=S.|last5=Borkhardt|first5=A.|last6=Karawajew|first6=L.|last7=Ratei|first7=R.|last8=Ruppert|first8=V.|last9=Haferlach|first9=T.|date=2000|title=Detection of acute leukemia cells with mixed lineage leukemia (MLL) gene rearrangements by flow cytometry using monoclonal antibody 7.1|url=https://www.ncbi.nlm.nih.gov/pubmed/10914547|journal=Leukemia|volume=14|issue=7|pages=1232–1238|doi=10.1038/sj.leu.2401840|issn=0887-6924|pmid=10914547}}</ref>
CD34, CD117, and CD56 (adult)<ref name=":2" />
|-
|Negative (universal)||CD13, CD34, and CD14 (children)<ref>{{Cite journal|last=Creutzig|first=U.|last2=Harbott|first2=J.|last3=Sperling|first3=C.|last4=Ritter|first4=J.|last5=Zimmermann|first5=M.|last6=Löffler|first6=H.|last7=Riehm|first7=H.|last8=Schellong|first8=G.|last9=Ludwig|first9=W. D.|date=1995|title=Clinical significance of surface antigen expression in children with acute myeloid leukemia: results of study AML-BFM-87|url=https://www.ncbi.nlm.nih.gov/pubmed/7579404|journal=Blood|volume=86|issue=8|pages=3097–3108|issn=0006-4971|pmid=7579404}}</ref>
|-
|Negative (subset)||None
|}

==Chromosomal Rearrangements (Gene Fusions)==

Put your text here and fill in the table

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference)
|Yes
|No
|Yes
|EXAMPLE

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).
|}		
			

<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}

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>.

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|t(9;11)(p21.3;q23.3)||5'KMT2A / 3'MLLT3||der(11)||1-12% of AML
|}

</blockquote>


<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}

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.

</blockquote>
==Individual Region Genomic Gain / Loss / LOH==

Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>

{| class="wikitable sortable"
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE

7
|EXAMPLE Loss
|EXAMPLE

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

chr7
|Yes
|Yes
|No
|EXAMPLE

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).
|-
|EXAMPLE

8
|EXAMPLE Gain
|EXAMPLE

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

chr8
|No
|No
|No
|EXAMPLE

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

<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}

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" />.

{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|-
|8||Gain (trisomy)||Entire chromosome
|}

</blockquote>
==Characteristic Chromosomal Patterns==

Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis'')</span>

{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE

Co-deletion of 1p and 18q
|Yes
|No
|No
|EXAMPLE:

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

<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}

Not applicable

</blockquote>
==Gene Mutations (SNV / INDEL)==

Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'') </span>

{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE: TP53; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations
|EXAMPLE: TSG
|EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)
|EXAMPLE: IDH1 R123H
|EXAMPLE: EGFR amplification
|
|
|
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
<br />
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
NA

===Other Mutations===
NA

</blockquote>
==Epigenomic Alterations==

Not applicable

==Genes and Main Pathways Involved==

Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|EXAMPLE: MAPK signaling
|EXAMPLE: Increased cell growth and proliferation
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|EXAMPLE: Cell cycle regulation
|EXAMPLE: Unregulated cell division
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|EXAMPLE:  Histone modification, chromatin remodeling
|EXAMPLE:  Abnormal gene expression program
|}

<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}

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>.

</blockquote>
==Genetic Diagnostic Testing Methods==
Karyotype, FISH, RT-PCR

==Familial Forms==
Not applicable

==Additional Information==
Not applicable

==Links==

[[KMT2A]]

[[MLLT3]]

==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <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>''Citation of this Page'': “Acute myeloid leukaemia with KMT2A rearrangement”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_KMT2A_rearrangement</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases A]]