RNA sequencing reveals a unique fusion of the lysine (K)-specific methyltransferase 2A and smooth muscle myosin heavy chain 11 in myelodysplastic syndrome and acute myeloid leukemia.

RNA sequencing reveals a unique fusion of the lysine (K)-specific methyltransferase 2A and smooth muscle myosin heavy chain 11 in myelodysplastic syndrome and acute myeloid leukemia Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are heterogeneous malignancies characterized by a variety of acquired genetic abnormalities and variable response to treatment. 1,2 In the last decade, a number of novel molecular genetic abnormalities have been revealed in MDS and AML by applying novel genome-wide technologies, such as massively parallel sequencing. The different recurrent genetic aberrations shed light on possible mechanisms involved in leukemogenesis and refine risk stratification of both diseases. 1 Although recurrence of aberrations in MDS and AML is the major guide to reveal general mechanisms regarding leukemogenesis, unique abnormalities can also be highly informative. Here we describe a unique fusion of the lysine (K)-specific methyltransferase 2A (KMT2A) gene [mixed-lineage leukemia gene (MLL)], located on chromosome 11q23, and the gene encoding smooth muscle myosin heavy chain 11 (MYH11), located on chromosome 16p13, in a patient with MDS and subsequently AML, both harboring the cryptic translocation t(11;16). KMT2A and MYH11 are involved in recurrent translocations in AML, but fusions of these two genes have never been demonstrated. KMT2A is a transcriptional activator, which regulates gene expression, including HOX genes, by methylation of histone H3 lysine 4 (H3K4). 4 The KMT2A gene on 11q23 is involved in translocations in approximately 5% of adult AML cases 4 and more than 70 translocation partners of KMT2A have been described. 5 The majority of KMT2A fusions incorporate the N-terminal portion of KMT2A, containing three short AT-hook motifs, two speckled nuclear localization sites, and a transcriptional repression domain (Figure 1B). 4,5 Leukemic KMT2A fusions impair H3K4 methylation and transform hematopoietic cells very efficiently. MYH11 is a subunit of a major contractile protein consisting of two heavy chain subunits and two pairs of non-identical light chain subunits. A pericentric inversion or translocation of chromosome 16 (inv(16)(p13q22) or t(16;16)(p13;q22)), involving the MYH11 gene, defines a specific subtype of AML characterized by eosinophilia and favorable treatment outcome, and is characteristic for core-binding factor (CBF) leukemias. 1 These chromosome 16 abnormalities result in the fusion of MYH11 and core-binding factor β (CBFB) on 16q22. The resulting fusion transcript CBFB-MYH11 encodes a protein consisting of the first 133-165 residues of the N-terminus of CBFB and variable C-terminal portions of MYH11. There are two models proposed for CBF-leukemogenesis both based on impairment …