Bone marrow neoplastic
Bone marrow - neoplastic myeloid
AML with other rare recurrent translocations
AML (megakaryoblastic) with t(1;22)(p13.3;q13.1); RBM15::MRTF1
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PubMed Search: AML t1;22
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Positive stains | Negative stains | Flow cytometry description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Cite this page: Hamnvåg HM, Mirza KM. AML (megakaryoblastic) with t(1;22)(p13.3;q13.1); RBM15::MRTF1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowneoplasticAMLmegakaryoblastic.html. Accessed December 22nd, 2024.
Definition / general
- Rare type of acute myeloid leukemia (megakaryoblastic) with a megakaryocytic phenotype (AMKL)
- Described as an entity under the category of acute myeloid leukemia with recurrent genetic abnormalities in the revised 2016 WHO Classification (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017)
- Acute megakaryoblastic leukemia with t(1;22)(p13.3;q13.1) resulting in fusion of RBM15 and MKL1 genes
Essential features
- Rare subtype of AML with recurrent genetic abnormalities and differentiation along the megakaryocytic lineage
- Defined by t(1:22)(p13.3;q13.1); RBM15-MKL1
- Blasts are positive for platelet specific markers CD41a+, CD42b+, CD61+
- Occurs most commonly de novo in infants and young children (aged ≤ 3 years) without Down syndrome
- Severe disease often with poor prognosis
Terminology
- Acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13.3;q13.1); RBM15-MKL1
- AMKL with t(1:22)(p13.3;q13.1); RBM15-MKL1
- RBM15 and MKL1 are also referred to as OTT and MAL, respectively
- Abbreviations RBM15, MKL1, OTT and MAL stand for RNA binding motif protein 15, megakaryoblastic leukemia 1, OneTwoTwo and megakaryoblastic acute leukemia
ICD coding
- ICD-O: 9911/3 - Acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
Epidemiology
- Represents < 1% of all cases of AML
- Occurs most commonly in infants and young children (aged ≤ 3 years) without Down syndrome
- Most cases occur in the first 6 months of life (median patient age: 4 months)
- Female predominance
- Congenital cases have been described (Am J Hematol 2015;90:963, Cancer Genet Cytogenet 1988;34:277, J Pediatr Hematol Oncol 1999;21:428)
Sites
- Bone marrow, spleen and liver
- Lymph node involvement can also occur
Etiology
- Postulated normal counterpart: myeloid progenitor cell with predominant megakaryocytic differentiation
- RBM15-MKL1 fusion gene arising from the t(1;22)(p13.3;q13.1) is thought to be the initiating event (Blood 2015;126:943, Nat Genet 2001;28:220)
- RBM15 encodes a protein with RNA recognizing motifs and a split end paralogue and orthologue C terminal (SPOC) domain that interact with the SMRT and NCoR corepressor complexes and the transcription factor downstream of Notch signaling named RBPJ (EMBO J 2002;21:5417, Genes Dev 2003;17:1909)
- Product of MKL1 acts as a transcriptional coactivator of serum response factor (SRP), a transcription factor that regulates genes involved in cell growth, proliferation, differentiation and genes controlling the actin cytoskeleton (Blood 2010;116:1942)
- Fusion of RBM15 and MKL1 may influence chromatin organization, differentiation induced by the HOX pathway and extracellular signaling pathways (Proc Natl Acad Sci USA 2001;98:5776)
Clinical features
- Majority of cases present with marked hepatosplenomegaly
- Patients have anemia and usually thrombocytopenia and moderately elevated white cell count
- Can present as a liver mass mimicking hepatoblastoma or severe hepatic failure (Pediatr Blood Cancer 2020;67:e28111, Glob Pediatr Health 2017;4:2333794X16689011)
- Lymphadenopathy and ascites have also been described upon presentation (Blood 1991;78:748)
Diagnosis
- Bone marrow biopsy
- Cytogenetics
- Molecular genetics
- Immunophenotyping
- Karyotype analysis showing evidence of t(1;22)(p13.3:q13.1) or molecular genetic evidence demonstrating RBM15-MKL1 fusion
Prognostic factors
- Some studies have suggested that patients treated with intensive AML chemotherapy respond well, with long disease free survival (Leukemia 2000;14:216, Leuk Lymphoma 2003;44:49)
- However, the overall evidence suggests that it has a worse prognosis compared with other pediatric acute megakaryocytic leukemia, including those associated with Down syndrome (Leukemia 2000;14:216, Blood 1991;78:748, Blood 2015;126:1575, Ann Hematol 2015;94:1327)
Case reports
- 10 day old girl presented with an epistaxis (Am J Hematol 2015;90:963)
- 1 month old girl with RBM15-MKL1 presenting as severe hepatic failure (Glob Pediatr Health 2017;4:2333794X16689011)
- 2 month old twin girls presented with fever and poor feeding and subsequently developed hepatosplenomegaly (J Pediatr Hematol Oncol 1999;21:428)
- 4 month old girl with AMKL where detection of RBM15-MKL1 fusion was useful for diagnosis and monitoring of minimal residual disease (Acta Med Okayama 2014;68:119)
- 11 month old Caucasian boy with AML mimicking hepatoblastoma (Pediatr Blood Cancer 2020;67:e28111)
Treatment
- Chemotherapy (combination of an anthracycline and cytarabine)
Microscopic (histologic) description
- Mixture of small and large megakaryoblasts may be found in the bone marrow and peripheral blood together with more undifferentiated blast cells with high N:C ratio
- Megakaryoblasts are most often medium sized to large (12 - 18 μm)
- Nucleus is round, slightly irregular / indented with fine reticular chromatin and 1 - 3 nucleoli
- Cytoplasm is basophilic, often agranular, with distinct blebs or pseudopod formation
- Bone marrow is normocellular to hypercellular, with varying degrees of reticulin and fibrosis
- Dense fibrosis may result in a pattern of infiltration mimicking metastatic tumor (Leukemia 2000;14:216, Blood 1991;78:748)
- Establishing the presence of ≥ 20% blasts on bone marrow aspirate may prove difficult due to extensive fibrosis; making correlation with bone marrow biopsy findings crucial
- Micromegakaryocytes are commonly present
- Dysplastic erythroid and granulocytic cells are usually not seen
Positive stains
Negative stains
- TdT
- Myeloperoxidase antibodies
- CD34
- CD45
- HLA-DR
- Cytochemical staining for Sudan Black B and myeloperoxidase is consistently negative
Flow cytometry description
- Blasts are CD41a+, CD42b+, CD61+
Molecular / cytogenetics description
- Translocation t(1;22)(p13.3;q13.1) is visible on karyotype (Nat Genet 2001;28:220)
- Detection of RBM15-MRTFA (MKL1) fusion transcript via RT-PCR
Sample pathology report
- Right posterior iliac crest, core biopsy, aspirate smear, touch imprint and clot particle:
- Acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13.3;q13.1); RBM15-MKL1 (see comment)
- Comment: The bone core biopsy demonstrates extensive replacement of marrow by blast cells in areas arranged into clusters and aggregates surrounded by fibrotic stroma. The marrow aspirate smears reveal a heteromorphic population of blasts. Blast phenoptyping with immunohistochemical stains and flow cytometry analysis reveal positivity for markers of megakaryocytic maturation. Cytogenetics evaluation reveals t(1;22)(p13.3;q13.1), confirming above diagnosis.
Differential diagnosis
- Non-Down syndrome associated acute megakaryoblastic leukemia:
- AMKL with CBFA2T3-GLIS2 fusion
- AMKL with NUP98-KDM5A fusion
- Acute myeloid leukemia associated with Down syndrome:
- GATA1 mutation is present
- t(1;22) translocation is not present
- Hepatoblastoma
Board review style question #1
What is the resulting fusion gene product in t(1;22)(p13.3;q13.1) that is recurrent in one of the acute leukemic entities?
- DEK-NUP214
- KMT2A-MLLT3
- PML-RARA
- RBM15-MKL1
- RUNX1-RUNX1T1
Board review style answer #1
Board review style question #2
Which of the following populations have the highest incidence of acute megakaryoblastic leukemia (AMKL) with t(1;22)(p13.3;q13.1)?
- Children aged 5 - 10
- Elderly females
- Elderly males
- Infants with Down syndrome
- Infants without Down syndrome
Board review style answer #2
E. Infants without Down syndrome
Comment Here
Reference: AML (megakaryoblastic) with t(1;22)(p13.3;q13.1)
Comment Here
Reference: AML (megakaryoblastic) with t(1;22)(p13.3;q13.1)
Board review style question #3
Which of the following markers is mostly likely to be negative in AMKL with t(1;22)(p13.3;q13.1)?
- CD13
- CD36
- CD41
- CD61
- Myeloperoxidase
Board review style answer #3
