Frequent pathway mutations of splicing machinery in myelodysplasia

Abstract

Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (∼45 to ∼85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

“…Potential targets of miR-575 are the serine/arginine-rich splicing factors SFRS2 (also known as SRSF2) and SFRS1 (also known as SRSF1), which are members of pre-mRNA splicing factors and constitute part of the spliceosome. An SRSF2 mutation is present in ~12% of patients with myelodysplastic syndromes [44][45][46] and frequently mutated in MDS/MPN patients (24%), particularly in CMML (28%) [47]. Although not common in the classic MPNs, SRSF2 mutations are more common in acute myeloid leukemia transformed from MPNs (18.9%) compared with leukemia transformation after myelodysplasia (4.8%) or de novo AML (5.6%) [48].…”

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

“…Similarly, these mutations are seen in a small fraction (<10%) of patients with primary myelofibrosis (PMF), are strongly associated with the presence of BM RS, but do not affect disease outcome [17]. SRSF2 mutations are seen in patients with MDS, CMML, MPN/PMF, and acute myeloid leukemia (AML) [12,13,16,[18][19][20], and are very rare in juvenile myelomonocytic leukemia [19,21]. In MDS and PMF, SRSF2 mutations are relatively common ( 15-20%) and are associated with shortened OS and LFS [16,18,22].…”

“…Thus far, in CMML, loss-of-function mutations involving EZH2 and ASXL1 have been associated with poor outcomes [10,11]. The data with regard to the other mutations needs further elucidation.Mutations in genes of the splicing machinery, such as SF3B1 (splicing factor 3B, subunit 1), SRSF2 (serine/arginine-rich splicing factor 2) and U2AF35, also known as U2AF1 (U2 small nuclear RNA auxiliary factor) are common in patients with myeloid malignancies [12][13][14]. SF3B1 mutations have a high prevalence ( 80%) in MDS and ring sideroblasts (RS) and do not influence either OS or leukemiafree survival (LFS) [15,16].…”

“…Similarly, these mutations are seen in a small fraction (<10%) of patients with primary myelofibrosis (PMF), are strongly associated with the presence of BM RS, but do not affect disease outcome [17]. SRSF2 mutations are seen in patients with MDS, CMML, MPN/PMF, and acute myeloid leukemia (AML) [12,13,16,[18][19][20], and …”

L’épissage des ARN pré-messagers : quand le splicéosome perd pied

“…Certaines de ces mutations ont été décrites comme des mutations pilotes (drivers) oncogéniques. De façon remarquable, dans les syndromes myélodysplasiques (SMD), des hémopathies malignes pouvant évoluer en leucémie aiguë myéloïde (LAM), plus de la moitié des patients présentent une mutation acquise dans un gène codant une protéine d'épissage [24]. L'un des facteurs les plus fréquemment mutés est SF3B1 (splicing factor 3b subunit 1), dans 20 % des syndromes myélodysplasiques (SMD), et jusqu'à 80 % dans les formes sidé-roblastiques, caractérisées par la présence de sidéroblastes en couronne dans la moelle osseuse 3 [25] …”