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

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


{{Under Construction}}
{{Under Construction}}


<blockquote class='blockedit'>{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|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 class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|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]].
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|Subtype(s)
|Subtype(s)
|Acute myeloid leukaemia with KMT2A rearrangement
|Acute myeloid leukaemia with KMT2A rearrangement
|}
==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. Do not delete table.'') </span>
{| class="wikitable"
|'''Signs and Symptoms'''
|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)
<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)
<span class="blue-text">EXAMPLE:</span> Fatigue
<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|<span class="blue-text">EXAMPLE:</span> Cytopenias
<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
|}
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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==
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
|}
|}


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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>.
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">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 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 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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<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
<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)
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* 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" />.
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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Not applicable
Not applicable
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|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


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NA
NA


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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>.
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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'''
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==Notes==
==Notes==
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<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>.
<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]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases A]]