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

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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

↑ ^1.0 ^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.
↑ ^2.0 ^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.
↑ 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)
↑ 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.
↑ ^5.0 ^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.
↑ 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)
↑ 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)
↑ 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)
↑ ^9.0 ^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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.

[:1-1] 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.

[:3-2] 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.

[:4-5] 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] 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)

[:2-9] 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)

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@@ Line 1: / Line 1: @@
 {{DISPLAYTITLE:Acute myeloid leukaemia with RBM15::MRTFA fusion}}
 [[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
-{{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) Megakaryoblastic with t(1;22)(p13.3;q13.1);RBM15-MKL1]].
-}}</blockquote>
 ==Primary Author(s)*==
@@ Line 33: / Line 27: @@
 |}
-==WHO Essential and Desirable Genetic Diagnostic Criteria==
-{| class="wikitable"
-|+
-|WHO Essential Criteria (Genetics)*
-|Detection of ''RBM15''::''MRTFA'' fusion by FISH and/or RT-PCR or a similar molecular technique
-|-
-|WHO Desirable Criteria (Genetics)*
-|Detection of t(1;22)(p13.3;q13.1) by karyotype analyssi
-|-
-|Other Classification
-|N/A
-|}
-<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
 ==Related Terminology==
-<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
 {| class="wikitable"
 |+
 |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
 |}
@@ Line 67: / Line 48: @@
 |-
 |''RBM15'' and ''MKL1''
-|''RBM15''(''OTT'') / ''MKL1''(''MAL'')||The majority of both genes retained in the fusion 5’ ''DEK'' and 3’''NUP214''(''CAN'') with the pathogenic derivative being hte der(22).||t(1;22)(p13.3;q13.1)
+|''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 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" />.
+*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" />.
-* Typically the ''RBM15''-''MKL1'' fusion presents as the sole abnormality<ref name=":3" />.
+*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>.
-* 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>.
+*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" />.
+*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" />.
-* The t(1;22) was originally associated with poor prognosis but some studies demonstrate good response to intensive chemotherapy with long disease-free survival<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=":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 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>.  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" />.
+*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"
 |-
-!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
+!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'''
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
-!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
-!'''Clinical Relevance Details/Other Notes'''
+!Clinical Relevance Details/Other Notes
 |-
 |N/A
@@ Line 100: / Line 81: @@
 !Chromosomal Pattern
 !Molecular Pathogenesis
-!'''Prevalence -'''
+!Prevalence -
-'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
+Common >20%, Recurrent 5-20% or Rare <5% (Disease)
-!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
-!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
-!'''Clinical Relevance Details/Other Notes'''
+!Clinical Relevance Details/Other Notes
 |-
 |N/A
@@ Line 115: / Line 96: @@
 ==Gene Mutations (SNV/INDEL)==
-COSMIC does not have specific information on mutations related to this subtype of AML.
+*COSMIC does not have specific information on mutations related to this subtype of AML.
 {| class="wikitable sortable"
 |-
-!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
+!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
-'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
+Common >20%, Recurrent 5-20% or Rare <5% (Disease)
-!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
-!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
-!'''Clinical Relevance Details/Other Notes'''
+!Clinical Relevance Details/Other Notes
 |-
 |N/A
@@ Line 138: / Line 120: @@
 ==Genes and Main Pathways Involved==
-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">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><ref name=":1" />.
+*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>.
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
 {| class="wikitable sortable"
 |-
 !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 |-
-|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
+|''RBM15'' and ''MKL1''; Gain-of-function
-|<span class="blue-text">EXAMPLE:</span> MAPK signaling
+|HOX and other signaling pathways
-|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
+|Abnormal megakaryopoiesis
-|-
-|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
-|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
-|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
-|-
-|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
-|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
-|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
-|-
-|
-|
-|
 |}
 ==Genetic Diagnostic Testing Methods==
-Karyotype, FISH, RT-PCR
+Karyotype, FISH, RT-PCR (and any other fusion detecting technologies)
 ==Familial Forms==
@@ Line 179: / Line 149: @@
 ==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 where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. 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. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />
+<references />
 <br />

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

Latest revision as of 12:08, 3 July 2025

Primary Author(s)*

WHO Classification of Disease

Related Terminology

Gene Rearrangements

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal or Other Global Mutational Patterns

Gene Mutations (SNV/INDEL)

Epigenomic Alterations

Genes and Main Pathways Involved

Genetic Diagnostic Testing Methods

Familial Forms

Additional Information

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References

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