HAEM4Backup: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
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
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)
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 |
Characteristic Chromosomal Aberrations / Patterns
Not applicable
Genomic Gain/Loss/LOH
Not applicable
Gene Mutations (SNV/INDEL)
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 |
Epigenomics (Methylation)
Not applicable
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[1][2].
Diagnostic Testing Methods
Karyotype, FISH, RT-PCR
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
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].
Familial Forms
Not applicable
Other Information
Not applicable
Links
References
- ↑ 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.
- ↑ 2.0 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.
- ↑ 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.
- ↑ 4.0 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.
- ↑ 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.
- ↑ 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
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