Acute myeloid leukaemia with RBM15::MRTFA fusion

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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

WHO Essential and Desirable Genetic Diagnostic Criteria

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 analysis
Other Classification N/A

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

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

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

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*Citation of this Page: “Acute myeloid leukaemia with RBM15::MRTFA fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 05/13/2025, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_RBM15::MRTFA_fusion.

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