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Frequency and prognostic impact of casein kinase 1A1 mutations in MDS patients with deletion of chromosome 5q

Leukemia volume 29, pages 1942–1945 (2015)Cite this article

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Recently, missense mutations in casein kinase 1A1 (CSNK1A1) have been described in individual patients with myelodysplastic syndrome (MDS) and deletion of 5q (n=4)1, 2 and in a patient with MDS and a normal karyotype (n=1).3 The serine–threonine kinase casein kinase 1α (CK1α) is encoded by CSNK1A1 and is located in the common deleted region at 5q32. It has been described as a tumor suppressor gene in colon cancer and acute myeloid leukemia through regulation of β-catenin and TP53.4, 5, 6 CSNK1A1 mutations have been functionally characterized as non-loss-of-function mutations, as expression of mutant CK1α in CSNK1A1-null mice rescued hematopoiesis in these mice, which otherwise died from bone marrow failure.1 Mutant CK1α enhanced β-catenin expression but did not activate p53.1

Deletion of 5q is one of the most frequent cytogenetic aberrations in MDS and is associated with distinct clinical characteristics, disease course and sensitivity to lenalidomide. MDS with isolated deletion of 5q is a distinct entity in the 2008 World Health Organization (WHO) classification and patients mostly present with anemia, while platelet counts are often elevated. The common deleted region spans 1.5 Mb on 5q32 (ref. 7) and harbors 44 genes and 6 microRNAs. Haploinsufficiency of one of these genes, RPS14, has been shown to inhibit erythroid differentiation in vitro,8 whereas loss of miRNA-145 and miRNA-146 recapitulates thrombocytosis and megakaryocytic dysplasia in mice.9 Isolated deletion of 5q is associated with a favorable prognosis in MDS. However, the prognosis is less favorable, if a mutation in TP53 co-occurs in patients with del(5q) MDS.10 Symptomatic improvement and even cytogenetic remission can be achieved with lenalidomide, which is specifically active in MDS patients with 5q deletion.11 The purpose of the present study was to characterize the frequency and potential clinical impact of CSNK1A1 mutations in MDS and AML following MDS in a large cohort of patients.

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Acknowledgements

We are indebted to all patients and contributing doctors. This study was supported by grants 110284, 110287, 110292 and 111267 from Deutsche Krebshilfe; grant DJCLS R13/14 from the Deutsche José Carreras Leukämie-Stiftung eV; the German Federal Ministry of Education and Research grant 01EO0802 (IFB-Tx); DFG grant HE 5240/5-1 and HE 5240/6-1; and grants from Dieter-Schlag Stiftung.

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  1. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    M Heuser, M M A Cruz, J Fabisch, S Klesse, L Köhler, V Panagiota, C Koenecke, S Ehrlich, K Stamer & A Ganser

  2. MLL Munich Leukemia Laboratory, Munich, Germany

    M Meggendorfer, C Haferlach, T Haferlach & F Thol

  3. Institute of Human Genetics, Hannover Medical School, Hannover, Germany

    G Göhring & B Schlegelberger

  4. Department of Hematology and Oncology, Georg-August-Universität Göttingen, Göttingen, Germany

    C Ganster, K Shirneshan, A Gutermuth & D Haase

  5. Department of Hematology and Hemostasis, Medical University Vienna, Vienna, Austria

    S Cerny-Reiterer & P Valent

  6. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    J Krönke & K Döhner

  7. Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany

    U Platzbecker & C Thiede

  8. Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany

    T Schroeder & G Kobbe

  9. Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    N Kroeger

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  1. M Heuser
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Correspondence to M Heuser.

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Heuser, M., Meggendorfer, M., Cruz, M. et al. Frequency and prognostic impact of casein kinase 1A1 mutations in MDS patients with deletion of chromosome 5q. Leukemia 29, 1942–1945 (2015). https://doi.org/10.1038/leu.2015.49

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