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

Heuser, Michael; Meggendorfer, Manja; Cruz, Michelle; Fabisch, Jana; Klesse, Sabrina; Köhler, Lars; Göhring, Gudrun; Ganster, Christina; Shirneshan, Katayoon; Gutermuth, Annika; Cerny-Reiterer, Sabine; Krönke, Jan; Panagiota, Victoria; Haferlach, Claudia; Koenecke, Christian; Platzbecker, Uwe; Thiede, Christian; Schroeder, Thomas; Kobbe, Guido; Ehrlich, Steve; Stamer, Kathrin; Döhner, Konstanze; Valent, Peter; Schlegelberger, Brigitte; Ganser, Arnold; Haase, Detlef; Haferlach, Torsten; Thol, Felicitas

doi:10.1038/leu.2015.49

Cited by 19 publications

(19 citation statements)

References 13 publications

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“…The stabilization of components of cytokines and Wnt signaling by CSNK1E might be critical for hematopoietic cell self-renewal (Okamura et al 2004). Interestingly, mutations in a related casein kinase, CSNK1A1, are prevalent in MDS with del(5q), suggesting a role of this gene family in MDS pathogenesis (Schneider et al 2014;Heuser et al 2015). This functional information suggests that RASL-seq has captured splicing events with discriminatory power as well as clinical significance with novel insights into the pathogenic mechanisms underlying the development of MDS.…”

Section: Discussionmentioning

confidence: 99%

Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators

Qiu

Zhou

Thol

et al. 2016

RNA

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Myelodysplastic syndromes (MDS) are heterogeneous myeloid disorders with prevalent mutations in several splicing factors, but the splicing programs linked to specific mutations or MDS in general remain to be systematically defined. We applied RASL-seq, a sensitive and cost-effective platform, to interrogate 5502 annotated splicing events in 169 samples from MDS patients or healthy individuals. We found that splicing signatures associated with normal hematopoietic lineages are largely related to cell signaling and differentiation programs, whereas MDS-linked signatures are primarily involved in cell cycle control and DNA damage responses. Despite the shared roles of affected splicing factors in the 3 ′ splice site definition, mutations in U2AF1, SRSF2, and SF3B1 affect divergent splicing programs, and interestingly, the affected genes fall into converging cancer-related pathways. A risk score derived from 11 splicing events appears to be independently associated with an MDS prognosis and AML transformation, suggesting potential clinical relevance of altered splicing patterns in MDS.

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Section: Discussionmentioning

confidence: 99%

Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators

Qiu

Zhou

Thol

et al. 2016

RNA

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“…These mutations are associated similarly to the effect of TP53 mutations with rise to a poor prognosis in del(5q) MDS [56]. Other studies did not find impact of CSNK1A1 mutations on lenalidomide treatment in del(5q) MDS [57,58].…”

Section: Advance In Our Understanding Of Del(5q) Myelodysplastic Syndmentioning

confidence: 97%

Introductory Chapter: Progress in Myelodysplastic Syndrome Area

Fuchs¹

2019

Recent Developments in Myelodysplastic Syndromes

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“…The serine-thionine kinase, casein kinase 1α (CK1α), is encoded by casein kinase 1 A1 (CSNK1A1) gene [72,73]. CK1α has been implicated in the biology of del (5q) MDS and has been shown to be a therapeutic target in myeloid malignancies and is therefore an attractive candidate for mediating the effects of lenalidomide in del (5q) MDS [73].…”

Section: Lenalidomidementioning

confidence: 99%

“…CK1α has been implicated in the biology of del (5q) MDS and has been shown to be a therapeutic target in myeloid malignancies and is therefore an attractive candidate for mediating the effects of lenalidomide in del (5q) MDS [73]. CSNK1A1 gene is a putative tumor suppressor gene located in the CDR at 5q 32 for del (5q) MDS and is expressed at haploinsufficiency levels in MDS with del(5q) [72][73][74]. Haploinsufficiency of CSNK1A1 leads to hematopoietic stem-cell expansion in mice and may play a role in the initial clonal expansion in patients with 5q-syndrome [43].…”

Section: Lenalidomidementioning

confidence: 99%

Myelodysplastic Disorders, 5q-Syndrome

Al-Anazi¹

2016

Myelodysplastic Syndromes

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The myelodysplastic syndromes (MDSs) are characterized by ineffective erythropoiesis and progressive cytopenia and ultimately affected patients develop acute myeloid leukemia (AML) or die from advanced bone marrow (BM) failure. Myelodysplastic syndrome (MDS) with isolated del (5q) is a common type of MDS with specific pathological and clinical manifestations including refractory anemia. It is usually treated by (1) supportive measures including blood transfusions that may cause iron overload that requires iron chelation therapy, (2) targeted therapies such as the immunomodulatory drug lenalidomide, and (3) hematopoietic stem cell transplantation (HSCT) in transplant eligible individuals. The establishment of the various prognostic systems, the discovery of the new genetic mutations, and the identification of new targets, in MDSs in general and in 5q-syndrome in particular, will hopefully translate into more pinpointed targeted therapies that will further improve the outcomes of patients having these disorders.

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

Cited by 19 publications

References 13 publications

Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators

Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators

Introductory Chapter: Progress in Myelodysplastic Syndrome Area

Myelodysplastic Disorders, 5q-Syndrome

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