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MDS with deletions in the long arm of chromosome 11 are associated with a high frequency of SF3B1 mutations

Leukemia volume 31, pages 1995–1997 (2017)Cite this article

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Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell diseases mainly characterized by cytopenia and dysplasia in one or more of the major myeloid cell lines (Arber et al., 2016).1 Targeted sequencing of selected genes detected molecular mutations in 80–90% of MDS patients, most commonly including genes involved in epigenetic regulation, transcription factors and components of the RNA-splicing machinery (TET2, ASXL1, DNMT3A, EZH2, RUNX1, TP53, U2AF1, SF3B1 and SRSF2).2, 3, 4 Chromosomal abnormalities are also common in MDS, as ~50% of MDS cases exhibit cytogenetic aberrations. In contrast to AML, the majority of abnormalities are unbalanced, most frequently including −5/5q−, −7/7q−, +8, 20q−, −18/18q− and −Y.5, 6 However, these aberrations comprise only ~40% of all cytogenetic abnormalities detected in MDS, as ~60% of abnormalities are rare, that is, occurring with a frequency of <2%.5 These include deletions in the long arm of chromosome 11 (del(11q)), which were observed with a frequency of 0.6–1.1%.7, 8, 9 Acquired cytogenetic aberrations are well established as independent prognostic factors in MDS, which are summarized in the (revised) International Prognostic Scoring System (IPSS, IPSS-R).8, 10 The IPSS-R distinguishes 19 cytogenetic categories providing clear prognostic classification in 91% of patients,8 categorizing the abnormalities into five prognostic subgroups (very good, good, intermediate, poor and very poor). Patients with MDS and del(11q) as sole abnormality were found to show a very good prognosis.8 Previous studies on 32 MDS patients with del(11q) with and without additional aberrations revealed a lack of cryptic KMT2A rearrangements and specific clinicopathologic features (transfusion-dependent anemia, ring sideroblasts, bone marrow hypocellularity and less severe thrombocytopenia).9 However, due to the rareness of this aberration in MDS patients, further molecular and clinical information regarding these cases has been limited.

We detected 33 cases with isolated del(11q) (del(11q)sole) and 23 cases with del(11q) accompanied by additional chromosomal aberrations (del(11q)other) by chromosome banding analyses11 out of 9225 unselected cases with de novo MDS. Samples (bone marrow and/or peripheral blood) were sent between April 2006 and January 2016 for diagnosis to the KMT2A Munich Leukemia Laboratory. The study followed the rules of the Helsinki Declaration and patients agreed with the use of laboratory data for research studies. Of the 33 MDS cases with del(11q)sole, 5 were classified as MDS-EB-1 (excess blasts), 2 MDS-EB-2 and 15 MDS-U (unclassifiable), 1 MDS-RS (ring sideroblasts), 2 MDS/MPN-RS-T (ring sideroblasts and thrombocytosis), 2 MDS-MLD (multilineage dysplasia) and 6 MDS-MLD-RS according to cytomorphology. The group including the 23 cases with del(11q)other contained 5 MDS-EB-1 cases, 2 MDS-EB-2 cases, 9 cases with MDS-U, 1 MDS-MLD and 3 MDS-MLD-RS, and 2 cases with 5q− syndrome. The cohort comprised 23 male and 33 female patients, median age was 75 years (range: 47–89 years). Diagnoses were assigned according to WHO classification,12 cytomorphology was available for all 56 cases and detailed data on immunophenotype for 29 patients. For 46 patients (33 of del(11q)sole and 13 of del(11q)other), material was available for investigation by genomic arrays (4 × 180 K microarray slides, Agilent Technologies, Santa Clara, CA, USA). In 45 cases (32 of del(11q)sole and 13 of del(11q)other), amplicon deep sequencing by next-generation sequencing was performed to detect mutations in ASXL1, CALR, CBL, CSF3R, CSNK1A1, DNMT3A, ETNK1, ETV6, EZH2, FLT3-TKD GATA1, GATA2, IDH1, IDH2, JAK, KIT, KRAS, MPL, NPM1, NRAS, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and ZRSR2. All genes were either sequenced on the 454 GS platform (454 Life Sciences, Branford, CT, USA), or were studied using a combination of a microdroplet-based assay (RainDance, Billerica, MA, USA) and the MiSeq sequencing instrument (Illumina, San Diego, CA, USA). SPSS (version 19.0.0) software (IBM Corporation, Armonk, NY, USA) was used for statistical analysis.

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Acknowledgements

We thank all co-workers at the MLL Munich Leukemia Laboratory for their technical assistance, and all physicians for providing and caring for patients as well as collecting data.

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  1. MLL Munich Leukemia Laboratory, Munich, Germany

    A Stengel, W Kern, M Meggendorfer, T Haferlach & C Haferlach

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  1. A Stengel
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Correspondence to A Stengel.

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CH, WK and TH declare part ownership of MLL Munich Leukemia Laboratory. AS and MM are employed by MLL Munich Leukemia Laboratory.

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Stengel, A., Kern, W., Meggendorfer, M. et al. MDS with deletions in the long arm of chromosome 11 are associated with a high frequency of SF3B1 mutations. Leukemia 31, 1995–1997 (2017). https://doi.org/10.1038/leu.2017.180

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