HAEM5:Acute myeloid leukaemia with RBM15::MRTFA fusion: Difference between revisions

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{{DISPLAYTITLE:Acute myeloid leukaemia with RBM15::MRTFA fusion}}
{{DISPLAYTITLE:Acute myeloid leukaemia with RBM15::MRTFA fusion}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


{{Under Construction}}
<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) Megakaryoblastic with t(1;22)(p13.3;q13.1);RBM15-MKL1]].
}}</blockquote>
==Primary Author(s)*==
==Primary Author(s)*==


Jennelle C. Hodge, PhD, FACMG
Jennelle C. Hodge, PhD, FACMG
==WHO Classification of Disease==


__TOC__
==Cancer Category / Type==
[[AML|Acute Myeloid Leukemia]]
==Cancer Sub-Classification / Subtype==
Acute myeloid leukemia (AML) Megakaryoblastic with t(1;22)(p13.3;q13.1) resulting in ''RBM15''-''MKL1'' 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, p139-140.</ref>.
==Synonyms / Terminology==
None.
==Epidemiology / Prevalence==
Accounts for <1% of AML, has a female predominance, can be congenital, and is restricted to infants and children below the age of 3 years (median onset of 4 months), most of whom do not have Down syndrome<ref name=":0" />.
==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"
{| class="wikitable"
|'''Signs and Symptoms'''
!Structure
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
!Disease
 
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.}}
 
Usually presents with marked organomegaly, especially hepatosplenomegaly, anemia, thrombocytopenia and a moderately elevated white blood cell count<ref name=":0" />.
 
</blockquote>
==Sites of Involvement==
 
Blood, bone marrow
 
==Morphologic Features==
 
This AML subtype generally has megakaryocyte lineage maturation in a normocellular to hypercellular marrow, often with reticulin and collagenous fibrosis<ref name=":0" />.  The blasts are similar to those of acute megakaryoblastic leukemia.  Small and large megakaryoblasts can be present and some cases have admixture with more morphologically undifferentiated blasts that have a high nuclear-cytoplasmic ratio (resemble lymphoblasts).  The megakaryoblasts are usually medium to large (12-18 μm), have a slightly irregular or indented and round nucleus with fine reticular chromatin, one to three nucleoli, basophilic and often agranular cytoplasm, and may have distinct blebs or pseudopod formation.  Micromegakaryocytes are common, dysplastic features of granulocytic and erythroid cells are not typically present, and some cases have a stromal pattern of bone marrow infiltration that mimics a metastatic tumor<ref name=":0" />.
 
It may be difficult to identify the minimum diagnostic criteria of 20% blasts in an aspirate in cases involving a fibrotic marrow.  Correlation with bone marrow biopsy results is important in such cases<ref name=":0" />.
 
==Immunophenotype==
 
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
|Book
|Haematolymphoid Tumours (5th ed.)
|-
|-
|Positive (universal)||CD36, CD41 (glycoprotein IIb/IIIa) and/or CD61 (glycoprotein IIIa) and/or less frequently CD42b (glycoprotein Ib)
|Category
|Myeloid proliferations and neoplasms
|-
|-
|Positive (subset)||CD13, CD33
|Family
|Acute myeloid leukaemia
|-
|-
|Negative (universal)||Sudan Black B (SBB) and Myeloperoxidase (MPO), Terminal Deoxynucleotidyl Transferase (TdT), lymphoid markers
|Type
|Acute myeloid leukaemia with defining genetic abnormalities
|-
|-
|Negative (subset)||CD34, CD45, HLA-DR
|Subtype(s)
|Acute myeloid leukaemia with RBM15::MRTFA fusion
|}
|}


==Chromosomal Rearrangements (Gene Fusions)==
==Related Terminology==


Put your text here and fill in the table
{| class="wikitable"
 
|+
{| class="wikitable sortable"
|Acceptable
|Acute megakaryoblastic leukaemia with RBM15::MRTFA
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|Not Recommended
!Diagnostic Significance (Yes, No or Unknown)
|Acute myeloid leukaemia with RBM15::MKL1; acute megakaryoblastic leukaemia with RBM15::MKL1; acute myeloid leukaemia with OTT::MAL
!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 presence of a t(1;22)(p13.3;q13.1), which results in fusion of ''RBM15''(''OTT'') at 1p13.3 [hg38] and ''MKL1''(''MAL'') at 22q13.1 [hg38] with variable breakpoints<ref name=":1">{{Cite journal|last=Ma|first=Z.|last2=Morris|first2=S. W.|last3=Valentine|first3=V.|last4=Li|first4=M.|last5=Herbrick|first5=J. A.|last6=Cui|first6=X.|last7=Bouman|first7=D.|last8=Li|first8=Y.|last9=Mehta|first9=P. K.|date=2001|title=Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/11431691|journal=Nature Genetics|volume=28|issue=3|pages=220–221|doi=10.1038/90054|issn=1061-4036|pmid=11431691}}</ref><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>.  Although both reciprocal fusions are expressed, the ''RBM15''-''MKL1'' fusion on the derivative chromosome 22 is the candidate oncoprotein because it contains all of the putative functional domains of both proteins<ref name=":1" />. Typically the ''RBM15''-''MKL1'' fusion presents as the sole abnormality<ref name=":0" />.


==Gene Rearrangements==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|t(1;22)(p13.3;q13.1)||RBM15(OTT) / MKL1(MAL) - majority of both genes retained in the fusion||der(22)||<1% of AML
|''RBM15'' and ''MKL1''
|}
|''RBM15''(''OTT'')::''MKL1''(''MAL'')||The majority of both genes are retained in the fusion, specifically 5’ ''DEK'' and 3’''NUP214''(''CAN''), with the pathogenic derivative being the der(22).||t(1;22)(p13.3;q13.1)
|Rare (AML)
</blockquote>
|D
 
|Yes (WHO)
 
|
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
*This AML subtype is characterized by megakaryocytic differentiation and is classified based on the presence by karyotype of a t(1;22)(p13.3;q13.1) or molecular confirmation of fusion of ''RBM15''(''OTT'') at 1p13.3 [hg38] and ''MKL1''(''MAL'') at 22q13.1 [hg38] with variable breakpoints<ref name=":1">{{Cite journal|last=Ma|first=Z.|last2=Morris|first2=S. W.|last3=Valentine|first3=V.|last4=Li|first4=M.|last5=Herbrick|first5=J. A.|last6=Cui|first6=X.|last7=Bouman|first7=D.|last8=Li|first8=Y.|last9=Mehta|first9=P. K.|date=2001|title=Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/11431691|journal=Nature Genetics|volume=28|issue=3|pages=220–221|doi=10.1038/90054|issn=1061-4036|pmid=11431691}}</ref><ref name=":3">WHO Classification of Tumours Editorial Board, eds, WHO Classification of Tumours, Haematolymphoid Tumours, 5th edition, IARC Press:Lyon, 2024.  Online at: [https://tumourclassification.iarc.who.int/welcome/ WHO Classification of Tumours].</ref><ref>{{Cite journal|last=Khoury|first=Joseph D.|last2=Solary|first2=Eric|last3=Abla|first3=Oussama|last4=Akkari|first4=Yassmine|last5=Alaggio|first5=Rita|last6=Apperley|first6=Jane F.|last7=Bejar|first7=Rafael|last8=Berti|first8=Emilio|last9=Busque|first9=Lambert|date=2022-07|title=The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/35732831|journal=Leukemia|volume=36|issue=7|pages=1703–1719|doi=10.1038/s41375-022-01613-1|issn=1476-5551|pmc=9252913|pmid=35732831}}</ref>.  Although both reciprocal fusions are expressed, the in-frame ''RBM15''::''MKL1'' fusion on the derivative chromosome 22 is the candidate oncoprotein because it contains all of the putative functional domains of both proteins<ref name=":1" />.
* Chromosomal Rearrangements (Gene Fusions)
*The ''RBM15''::''MKL1'' fusion typically presents as the sole abnormality<ref name=":3" />. A hyperdiploid karyotype with t(1;22) and +der(1)t(1;22) can be observed less frequently, typically in infants aged >6 months<ref>{{Cite journal|last=Carroll|first=A.|last2=Civin|first2=C.|last3=Schneider|first3=N.|last4=Dahl|first4=G.|last5=Pappo|first5=A.|last6=Bowman|first6=P.|last7=Emami|first7=A.|last8=Gross|first8=S.|last9=Alvarado|first9=C.|date=1991-08-01|title=The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a Pediatric Oncology Group Study|url=https://pubmed.ncbi.nlm.nih.gov/1859887|journal=Blood|volume=78|issue=3|pages=748–752|issn=0006-4971|pmid=1859887}}</ref>. Pediatric non-Down syndrome AMKL can arise through other genetic mechanisms that are unrelated to the ''RBM15''::''MKL1'' fusion<ref name=":4">{{Cite journal|last=de Rooij|first=Jasmijn D. E.|last2=Masetti|first2=Riccardo|last3=van den Heuvel-Eibrink|first3=Marry M.|last4=Cayuela|first4=Jean-Michel|last5=Trka|first5=Jan|last6=Reinhardt|first6=Dirk|last7=Rasche|first7=Mareike|last8=Sonneveld|first8=Edwin|last9=Alonzo|first9=Todd A.|date=2016|title=Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study|url=https://www.ncbi.nlm.nih.gov/pubmed/27114462|journal=Blood|volume=127|issue=26|pages=3424–3430|doi=10.1182/blood-2016-01-695551|issn=1528-0020|pmc=5161011|pmid=27114462}}</ref><ref>{{Cite journal|last=de Rooij|first=Jasmijn D. E.|last2=Branstetter|first2=Cristyn|last3=Ma|first3=Jing|last4=Li|first4=Yongjin|last5=Walsh|first5=Michael P.|last6=Cheng|first6=Jinjun|last7=Obulkasim|first7=Askar|last8=Dang|first8=Jinjun|last9=Easton|first9=John|date=2017-03|title=Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes|url=https://pubmed.ncbi.nlm.nih.gov/28112737|journal=Nature Genetics|volume=49|issue=3|pages=451–456|doi=10.1038/ng.3772|issn=1546-1718|pmc=5687824|pmid=28112737}}</ref>.
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}
 
Translocation-confirmed cases with <20% blasts on aspirate smears should be correlated with the biopsy to exclude an artificially low count due to marrow fibrosis, and then if the blasts remain low, followed closely to monitor for development of more definitive evidence for AML (such as the occurrence of extramedullary disease or myeloid sarcoma)<ref name=":0" />.
 
This translocation was originally associated with poor prognosis but some studies demonstrate good response to intensive chemotherapy with long disease-free survival<ref name=":0" />.  Two retrospective studies in 2015 and 2016 of non-Down syndrome pediatric AMKL patients found that the ''RBM15''-''MKL1'' fusion was present in 12% and 13.7% of cases, was associated with significantly younger onset, and was considered to have a relative risk classification of intermediate or standard<ref name=":2">{{Cite journal|last=Inaba|first=Hiroto|last2=Zhou|first2=Yinmei|last3=Abla|first3=Oussama|last4=Adachi|first4=Souichi|last5=Auvrignon|first5=Anne|last6=Beverloo|first6=H. Berna|last7=de Bont|first7=Eveline|last8=Chang|first8=Tai-Tsung|last9=Creutzig|first9=Ursula|date=2015|title=Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study|url=https://www.ncbi.nlm.nih.gov/pubmed/26215111|journal=Blood|volume=126|issue=13|pages=1575–1584|doi=10.1182/blood-2015-02-629204|issn=1528-0020|pmc=4582334|pmid=26215111}}</ref><ref>{{Cite journal|last=de Rooij|first=Jasmijn D. E.|last2=Masetti|first2=Riccardo|last3=van den Heuvel-Eibrink|first3=Marry M.|last4=Cayuela|first4=Jean-Michel|last5=Trka|first5=Jan|last6=Reinhardt|first6=Dirk|last7=Rasche|first7=Mareike|last8=Sonneveld|first8=Edwin|last9=Alonzo|first9=Todd A.|date=2016|title=Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study|url=https://www.ncbi.nlm.nih.gov/pubmed/27114462|journal=Blood|volume=127|issue=26|pages=3424–3430|doi=10.1182/blood-2016-01-695551|issn=1528-0020|pmc=5161011|pmid=27114462}}</ref>.  However, the majority of studies showed this to be a high-risk disease compared with pediatric AMKL without t(1;22).
 
Careful supportive care is likely required to prevent early death related to intensive chemotherapy<ref>{{Cite journal|last=Creutzig|first=Ursula|last2=Zimmermann|first2=Martin|last3=Reinhardt|first3=Dirk|last4=Dworzak|first4=Michael|last5=Stary|first5=Jan|last6=Lehrnbecher|first6=Thomas|date=2004|title=Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98|url=https://www.ncbi.nlm.nih.gov/pubmed/15514380|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=22|issue=21|pages=4384–4393|doi=10.1200/JCO.2004.01.191|issn=0732-183X|pmid=15514380}}</ref>, especially considering the very young age of patients with this AML subtype; differences in such care may cause the lack of prognostic consistency<ref name=":2" />.
 
</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>


*The t(1;22) occurs in <1% of all AML cases and 10-12% of pediatric acute megakaryoblastic leukemia cases<ref name=":4" />. It is most frequent in infants (<6 months old) and young children (<3 years old) with Down syndrome and has a female predominance. Rarely it occurs in adults<ref>{{Cite journal|last=Hsiao|first=Hui-Hua|last2=Yang|first2=Ming-Yu|last3=Liu|first3=Yi-Chang|last4=Hsiao|first4=Hui-Pin|last5=Tseng|first5=Shih-Bin|last6=Chao|first6=Mei-Chyn|last7=Liu|first7=Ta-Chih|last8=Lin|first8=Sheng-Fung|date=2005-05|title=RBM15-MKL1 (OTT-MAL) fusion transcript in an adult acute myeloid leukemia patient|url=https://pubmed.ncbi.nlm.nih.gov/15849773|journal=American Journal of Hematology|volume=79|issue=1|pages=43–45|doi=10.1002/ajh.20298|issn=0361-8609|pmid=15849773}}</ref><ref>{{Cite journal|last=Saito|first=Yo|last2=Makita|first2=Shinichi|last3=Chinen|first3=Shotaro|last4=Kito|first4=Momoko|last5=Fujino|first5=Takahiro|last6=Ida|first6=Hanae|last7=Hosoba|first7=Rika|last8=Tanaka|first8=Takashi|last9=Fukuhara|first9=Suguru|date=2020-09|title=Acute megakaryoblastic leukaemia with t(1;22)(p13·3;q13·1)/RBM15-MKL1 in an adult patient following a non-mediastinal germ cell tumour|url=https://pubmed.ncbi.nlm.nih.gov/32572949|journal=British Journal of Haematology|volume=190|issue=6|pages=e329–e332|doi=10.1111/bjh.16900|issn=1365-2141|pmid=32572949}}</ref>.
*Translocation-confirmed cases with <20% blasts on aspirate smears should be correlated with the biopsy to exclude an artificially low count due to marrow fibrosis, and then if the blasts remain low, followed closely to monitor for development of more definitive evidence for AML (such as the occurrence of extramedullary disease or myeloid sarcoma)<ref name=":3" />.
*Two retrospective studies in 2015 and 2016 of non-Down syndrome pediatric AMKL patients found that the ''RBM15::MKL1'' fusion was present in 12% and 13.7% of cases, was associated with significantly younger onset, and was considered to have a relative risk classification of intermediate or standard<ref name=":4" /><ref name=":2">{{Cite journal|last=Inaba|first=Hiroto|last2=Zhou|first2=Yinmei|last3=Abla|first3=Oussama|last4=Adachi|first4=Souichi|last5=Auvrignon|first5=Anne|last6=Beverloo|first6=H. Berna|last7=de Bont|first7=Eveline|last8=Chang|first8=Tai-Tsung|last9=Creutzig|first9=Ursula|date=2015|title=Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study|url=https://www.ncbi.nlm.nih.gov/pubmed/26215111|journal=Blood|volume=126|issue=13|pages=1575–1584|doi=10.1182/blood-2015-02-629204|issn=1528-0020|pmc=4582334|pmid=26215111}}</ref>.  However, the majority of studies showed this to be a high-risk disease compared with pediatric AMKL without t(1;22). Careful supportive care is likely required to prevent early death related to intensive chemotherapy<ref>{{Cite journal|last=Creutzig|first=Ursula|last2=Zimmermann|first2=Martin|last3=Reinhardt|first3=Dirk|last4=Dworzak|first4=Michael|last5=Stary|first5=Jan|last6=Lehrnbecher|first6=Thomas|date=2004|title=Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98|url=https://www.ncbi.nlm.nih.gov/pubmed/15514380|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=22|issue=21|pages=4384–4393|doi=10.1200/JCO.2004.01.191|issn=0732-183X|pmid=15514380}}</ref>, especially considering the very young age of patients with this AML subtype; differences in such care may cause the lack of prognostic consistency<ref name=":2" />. Presence of a hyperdiploid karyotype in pediatric AMKL, including the cases harboring another cytogenetic or molecular aberration, was an independent good prognostic factor for EFS but not for RFS or OS<ref name=":4" />.
|}
==Individual Region Genomic Gain/Loss/LOH==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
!Diagnostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Prognostic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Therapeutic Significance (Yes, No or Unknown)
!Clinical Relevance Details/Other Notes
!Notes
|-
|-
|EXAMPLE
|N/A
 
|
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).
|}
|}
 
==Characteristic Chromosomal or Other Global Mutational Patterns==
<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
 
Not applicable
 
</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"
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Molecular Pathogenesis
!Prognostic Significance (Yes, No or Unknown)
!Prevalence -
!Therapeutic Significance (Yes, No or Unknown)
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Notes
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE
|N/A
 
|
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).
|}
|}
==Gene Mutations (SNV/INDEL)==


<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}
*COSMIC does not have specific information on mutations related to this subtype of AML.
 
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"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!'''Diagnostic Significance (Yes, No or Unknown)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE: TP53; Variable LOF mutations
|N/A
 
|
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).
|}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.
<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.}}
 
COSMIC does not have specific information on mutations related to this subtype of AML.
===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||Not applicable
|-
|Secondary Mutations||Not applicable
|-
|Mutually Exclusive||Not applicable
|}
 
</blockquote>
==Epigenomic Alterations==
==Epigenomic Alterations==


Line 269: Line 120:
==Genes and Main Pathways Involved==
==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>
*The molecular mechanism is not completely understood, but the fusion protein may modulate chromatin organization, HOX-induced differentiation and extracellular signaling pathways associated with leukemogenesis<ref>{{Cite journal|last=Mercher|first=T.|last2=Coniat|first2=M. B.|last3=Monni|first3=R.|last4=Mauchauffe|first4=M.|last5=Nguyen Khac|first5=F.|last6=Gressin|first6=L.|last7=Mugneret|first7=F.|last8=Leblanc|first8=T.|last9=Dastugue|first9=N.|date=2001-05-08|title=Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/11344311|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=98|issue=10|pages=5776–5779|doi=10.1073/pnas.101001498|issn=0027-8424|pmc=33289|pmid=11344311}}</ref>.  The fusion of MKL1 to RBM15 deregulates the normal intracellular localization of MKL1 such that it is becomes constitutively localized to the nucleus, resulting in serum response factor (SRF) activation even in the absence of stimuli<ref>{{Cite journal|last=Gruber|first=Tanja A.|last2=Downing|first2=James R.|date=2015-08-20|title=The biology of pediatric acute megakaryoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/26186939|journal=Blood|volume=126|issue=8|pages=943–949|doi=10.1182/blood-2015-05-567859|issn=1528-0020|pmc=4551356|pmid=26186939}}</ref>. SRF is a transcription factor that regulates the expression of genes involved in cell growth, proliferation, and differentiation, as well as genes that control the actin cytoskeleton<ref>{{Cite journal|last=Halene|first=Stephanie|last2=Gao|first2=Yuan|last3=Hahn|first3=Katherine|last4=Massaro|first4=Stephanie|last5=Italiano|first5=Joseph E.|last6=Schulz|first6=Vincent|last7=Lin|first7=Sharon|last8=Kupfer|first8=Gary M.|last9=Krause|first9=Diane S.|date=2010-09-16|title=Serum response factor is an essential transcription factor in megakaryocytic maturation|url=https://pubmed.ncbi.nlm.nih.gov/20525922|journal=Blood|volume=116|issue=11|pages=1942–1950|doi=10.1182/blood-2010-01-261743|issn=1528-0020|pmc=3173990|pmid=20525922}}</ref>. Of note, while a ''RBM15''::''MKL1'' fusion knock-in model mouse showed abnormal megakaryopoiesis, it was not sufficient to induce leukemia<ref>{{Cite journal|last=Mercher|first=Thomas|last2=Raffel|first2=Glen D.|last3=Moore|first3=Sandra A.|last4=Cornejo|first4=Melanie G.|last5=Baudry-Bluteau|first5=Dominique|last6=Cagnard|first6=Nicolas|last7=Jesneck|first7=Jonathan L.|last8=Pikman|first8=Yana|last9=Cullen|first9=Dana|date=2009-04|title=The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model|url=https://pubmed.ncbi.nlm.nih.gov/19287095|journal=The Journal of Clinical Investigation|volume=119|issue=4|pages=852–864|doi=10.1172/JCI35901|issn=1558-8238|pmc=2662544|pmid=19287095}}</ref>.
 
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|''RBM15'' and ''MKL1''; Gain-of-function
|EXAMPLE: MAPK signaling
|HOX and other signaling pathways
|EXAMPLE: Increased cell growth and proliferation
|Abnormal megakaryopoiesis
|-
|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 molecular mechanism is not completely understand, but the fusion protein may modulate chromatin organization, HOX-induced differentiation and extracellular signaling pathways<ref name=":0" /><ref name=":1" />.
</blockquote>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


Karyotype, FISH, RT-PCR
Karyotype, FISH, RT-PCR (and any other fusion detecting technologies)


==Familial Forms==
==Familial Forms==
Line 311: Line 149:


==References==
==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 />
<references />


'''
<br />


==Notes==
==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>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 [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
 
Prior Author(s): 
 
       
<nowiki>*</nowiki>''Citation of this Page'': “Acute myeloid leukaemia with RBM15::MRTFA fusion”. 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_RBM15::MRTFA_fusion</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Acute myeloid leukaemia with RBM15::MRTFA fusion”. 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_RBM15::MRTFA_fusion</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases A]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases A]]

Latest revision as of 12:08, 3 July 2025

Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Jennelle C. Hodge, PhD, FACMG

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category Myeloid proliferations and neoplasms
Family Acute myeloid leukaemia
Type Acute myeloid leukaemia with defining genetic abnormalities
Subtype(s) Acute myeloid leukaemia with RBM15::MRTFA fusion

Related Terminology

Acceptable Acute megakaryoblastic leukaemia with RBM15::MRTFA
Not Recommended Acute myeloid leukaemia with RBM15::MKL1; acute megakaryoblastic leukaemia with RBM15::MKL1; acute myeloid leukaemia with OTT::MAL

Gene Rearrangements

Driver Gene Fusion(s) and Common Partner Genes Molecular Pathogenesis Typical Chromosomal Alteration(s) Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
RBM15 and MKL1 RBM15(OTT)::MKL1(MAL) The majority of both genes are retained in the fusion, specifically 5’ DEK and 3’NUP214(CAN), with the pathogenic derivative being the der(22). t(1;22)(p13.3;q13.1) Rare (AML) D Yes (WHO)
  • This AML subtype is characterized by megakaryocytic differentiation and is classified based on the presence by karyotype of a t(1;22)(p13.3;q13.1) or molecular confirmation of fusion of RBM15(OTT) at 1p13.3 [hg38] and MKL1(MAL) at 22q13.1 [hg38] with variable breakpoints[1][2][3]. Although both reciprocal fusions are expressed, the in-frame RBM15::MKL1 fusion on the derivative chromosome 22 is the candidate oncoprotein because it contains all of the putative functional domains of both proteins[1].
  • The RBM15::MKL1 fusion typically presents as the sole abnormality[2]. A hyperdiploid karyotype with t(1;22) and +der(1)t(1;22) can be observed less frequently, typically in infants aged >6 months[4]. Pediatric non-Down syndrome AMKL can arise through other genetic mechanisms that are unrelated to the RBM15::MKL1 fusion[5][6].
  • The t(1;22) occurs in <1% of all AML cases and 10-12% of pediatric acute megakaryoblastic leukemia cases[5]. It is most frequent in infants (<6 months old) and young children (<3 years old) with Down syndrome and has a female predominance. Rarely it occurs in adults[7][8].
  • Translocation-confirmed cases with <20% blasts on aspirate smears should be correlated with the biopsy to exclude an artificially low count due to marrow fibrosis, and then if the blasts remain low, followed closely to monitor for development of more definitive evidence for AML (such as the occurrence of extramedullary disease or myeloid sarcoma)[2].
  • Two retrospective studies in 2015 and 2016 of non-Down syndrome pediatric AMKL patients found that the RBM15::MKL1 fusion was present in 12% and 13.7% of cases, was associated with significantly younger onset, and was considered to have a relative risk classification of intermediate or standard[5][9]. However, the majority of studies showed this to be a high-risk disease compared with pediatric AMKL without t(1;22). Careful supportive care is likely required to prevent early death related to intensive chemotherapy[10], especially considering the very young age of patients with this AML subtype; differences in such care may cause the lack of prognostic consistency[9]. Presence of a hyperdiploid karyotype in pediatric AMKL, including the cases harboring another cytogenetic or molecular aberration, was an independent good prognostic factor for EFS but not for RFS or OS[5].

Individual Region Genomic Gain/Loss/LOH

Chr # Gain, Loss, Amp, LOH Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] Relevant Gene(s) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
N/A

Characteristic Chromosomal or Other Global Mutational Patterns

Chromosomal Pattern Molecular Pathogenesis Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
N/A

Gene Mutations (SNV/INDEL)

  • COSMIC does not have specific information on mutations related to this subtype of AML.
Gene Genetic Alteration Tumor Suppressor Gene, Oncogene, Other Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T   Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
N/A

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

Not applicable

Genes and Main Pathways Involved

  • The molecular mechanism is not completely understood, but the fusion protein may modulate chromatin organization, HOX-induced differentiation and extracellular signaling pathways associated with leukemogenesis[11]. The fusion of MKL1 to RBM15 deregulates the normal intracellular localization of MKL1 such that it is becomes constitutively localized to the nucleus, resulting in serum response factor (SRF) activation even in the absence of stimuli[12]. SRF is a transcription factor that regulates the expression of genes involved in cell growth, proliferation, and differentiation, as well as genes that control the actin cytoskeleton[13]. Of note, while a RBM15::MKL1 fusion knock-in model mouse showed abnormal megakaryopoiesis, it was not sufficient to induce leukemia[14].
Gene; Genetic Alteration Pathway Pathophysiologic Outcome
RBM15 and MKL1; Gain-of-function HOX and other signaling pathways Abnormal megakaryopoiesis

Genetic Diagnostic Testing Methods

Karyotype, FISH, RT-PCR (and any other fusion detecting technologies)

Familial Forms

Not applicable

Additional Information

Not applicable

Links

RBM15

MKL1

References

  1. ↑ 1.0 1.1 Ma, Z.; et al. (2001). "Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia". Nature Genetics. 28 (3): 220–221. doi:10.1038/90054. ISSN 1061-4036. PMID 11431691.
  2. ↑ 2.0 2.1 2.2 WHO Classification of Tumours Editorial Board, eds, WHO Classification of Tumours, Haematolymphoid Tumours, 5th edition, IARC Press:Lyon, 2024.  Online at: WHO Classification of Tumours.
  3. ↑ Khoury, Joseph D.; et al. (2022-07). "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms". Leukemia. 36 (7): 1703–1719. doi:10.1038/s41375-022-01613-1. ISSN 1476-5551. PMC 9252913 Check |pmc= value (help). PMID 35732831 Check |pmid= value (help). Check date values in: |date= (help)
  4. ↑ Carroll, A.; et al. (1991-08-01). "The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a Pediatric Oncology Group Study". Blood. 78 (3): 748–752. ISSN 0006-4971. PMID 1859887.
  5. ↑ 5.0 5.1 5.2 5.3 de Rooij, Jasmijn D. E.; et al. (2016). "Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study". Blood. 127 (26): 3424–3430. doi:10.1182/blood-2016-01-695551. ISSN 1528-0020. PMC 5161011. PMID 27114462.
  6. ↑ de Rooij, Jasmijn D. E.; et al. (2017-03). "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes". Nature Genetics. 49 (3): 451–456. doi:10.1038/ng.3772. ISSN 1546-1718. PMC 5687824. PMID 28112737. Check date values in: |date= (help)
  7. ↑ Hsiao, Hui-Hua; et al. (2005-05). "RBM15-MKL1 (OTT-MAL) fusion transcript in an adult acute myeloid leukemia patient". American Journal of Hematology. 79 (1): 43–45. doi:10.1002/ajh.20298. ISSN 0361-8609. PMID 15849773. Check date values in: |date= (help)
  8. ↑ Saito, Yo; et al. (2020-09). "Acute megakaryoblastic leukaemia with t(1;22)(p13·3;q13·1)/RBM15-MKL1 in an adult patient following a non-mediastinal germ cell tumour". British Journal of Haematology. 190 (6): e329–e332. doi:10.1111/bjh.16900. ISSN 1365-2141. PMID 32572949 Check |pmid= value (help). Check date values in: |date= (help)
  9. ↑ 9.0 9.1 Inaba, Hiroto; et al. (2015). "Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study". Blood. 126 (13): 1575–1584. doi:10.1182/blood-2015-02-629204. ISSN 1528-0020. PMC 4582334. PMID 26215111.
  10. ↑ Creutzig, Ursula; et al. (2004). "Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 22 (21): 4384–4393. doi:10.1200/JCO.2004.01.191. ISSN 0732-183X. PMID 15514380.
  11. ↑ Mercher, T.; et al. (2001-05-08). "Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia". Proceedings of the National Academy of Sciences of the United States of America. 98 (10): 5776–5779. doi:10.1073/pnas.101001498. ISSN 0027-8424. PMC 33289. PMID 11344311.
  12. ↑ Gruber, Tanja A.; et al. (2015-08-20). "The biology of pediatric acute megakaryoblastic leukemia". Blood. 126 (8): 943–949. doi:10.1182/blood-2015-05-567859. ISSN 1528-0020. PMC 4551356. PMID 26186939.
  13. ↑ Halene, Stephanie; et al. (2010-09-16). "Serum response factor is an essential transcription factor in megakaryocytic maturation". Blood. 116 (11): 1942–1950. doi:10.1182/blood-2010-01-261743. ISSN 1528-0020. PMC 3173990. PMID 20525922.
  14. ↑ Mercher, Thomas; et al. (2009-04). "The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model". The Journal of Clinical Investigation. 119 (4): 852–864. doi:10.1172/JCI35901. ISSN 1558-8238. PMC 2662544. PMID 19287095. Check date values in: |date= (help)


Notes

*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 Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):


*Citation of this Page: “Acute myeloid leukaemia with RBM15::MRTFA fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 07/3/2025, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_RBM15::MRTFA_fusion.

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