Acute myeloid leukaemia with RBM15::MRTFA fusion

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Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes
This page was converted to the new template on 2023-11-30. The original page can be found at HAEM4:Acute Myeloid Leukemia (AML) Megakaryoblastic with t(1;22)(p13.3;q13.1);RBM15-MKL1.

Primary Author(s)*

Jennelle C. Hodge, PhD, FACMG

Cancer Category / Type

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[1].

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[1].

Clinical Features

Put your text here and fill in the table (Instruction: Can include references in the table)

Signs and Symptoms EXAMPLE Asymptomatic (incidental finding on complete blood counts)

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

EXAMPLE Fatigue

EXAMPLE Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE Cytopenias

EXAMPLE Lymphocytosis (low level)


editv4:Clinical Features
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Usually presents with marked organomegaly, especially hepatosplenomegaly, anemia, thrombocytopenia and a moderately elevated white blood cell count[1].

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[1]. 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[1].

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[1].

Immunophenotype

Finding Marker
Positive (universal) CD36, CD41 (glycoprotein IIb/IIIa) and/or CD61 (glycoprotein IIIa) and/or less frequently CD42b (glycoprotein Ib)
Positive (subset) CD13, CD33
Negative (universal) Sudan Black B (SBB) and Myeloperoxidase (MPO), Terminal Deoxynucleotidyl Transferase (TdT), lymphoid markers
Negative (subset) CD34, CD45, HLA-DR

Chromosomal Rearrangements (Gene Fusions)

Put your text here and fill in the table

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE t(9;22)(q34;q11.2) EXAMPLE 3'ABL1 / 5'BCR EXAMPLE der(22) EXAMPLE 20% (COSMIC)

EXAMPLE 30% (add reference)

Yes No Yes EXAMPLE

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).


editv4:Chromosomal Rearrangements (Gene Fusions)
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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[2][3]. 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[2]. Typically the RBM15-MKL1 fusion presents as the sole abnormality[1].

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
t(1;22)(p13.3;q13.1) RBM15(OTT) / MKL1(MAL) - majority of both genes retained in the fusion der(22) <1% of AML


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)

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)[1].

This translocation was originally associated with poor prognosis but some studies demonstrate good response to intensive chemotherapy with long disease-free survival[1]. 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[4][5]. 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[6], especially considering the very young age of patients with this AML subtype; differences in such care may cause the lack of prognostic consistency[4].

Individual Region Genomic Gain / Loss / LOH

Put your text here and fill in the table (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.)

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE

7

EXAMPLE Loss EXAMPLE

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

EXAMPLE

chr7

Yes Yes No EXAMPLE

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

EXAMPLE

8

EXAMPLE Gain EXAMPLE

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

EXAMPLE

chr8

No No No EXAMPLE

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

editv4:Genomic Gain/Loss/LOH
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Not applicable

Characteristic Chromosomal Patterns

Put your text here (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)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE

Co-deletion of 1p and 18q

Yes No No EXAMPLE:

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

editv4:Characteristic Chromosomal Aberrations / Patterns
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Not applicable

Gene Mutations (SNV / INDEL)

Put your text here and fill in the table (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.)

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: TP53; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations

EXAMPLE: TSG EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)

EXAMPLE: IDH1 R123H EXAMPLE: EGFR amplification EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).


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.


editv4:Gene Mutations (SNV/INDEL)
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COSMIC does not have specific information on mutations related to this subtype of AML.

Other Mutations

Type Gene/Region/Other
Concomitant Mutations Not applicable
Secondary Mutations Not applicable
Mutually Exclusive Not applicable

Epigenomic Alterations

Not applicable

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Can include references in the table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations EXAMPLE:  Histone modification, chromatin remodeling EXAMPLE:  Abnormal gene expression program
editv4:Genes and Main Pathways Involved
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The molecular mechanism is not completely understand, but the fusion protein may modulate chromatin organization, HOX-induced differentiation and extracellular signaling pathways[1][2].

Genetic Diagnostic Testing Methods

Karyotype, FISH, RT-PCR

Familial Forms

Not applicable

Additional Information

Not applicable

Links

RBM15

MKL1

References

(use the "Cite" icon at the top of the page) (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. 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.)

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 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.
  2. 2.0 2.1 2.2 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. Arber, Daniel A.; et al. (2016). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–2405. doi:10.1182/blood-2016-03-643544. ISSN 1528-0020. PMID 27069254.
  4. 4.0 4.1 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.
  5. 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. 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.

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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “Acute myeloid leukaemia with RBM15::MRTFA fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 11/30/2023, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_RBM15::MRTFA_fusion.