Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes

Madan, Vikas; Li, Jia; Zhou, Shiwei; Teoh, Weoi Woon; Lin, Han; Meggendorfer, Manja; Malcovati, Luca; Cazzola, Mario; Ogawa, Seishi; Haferlach, Torsten; Yang, Henry; Koeffler, H. Phillip

doi:10.1002/ajh.25673

Cited by 16 publications

(19 citation statements)

References 57 publications

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“…introns [29]. Similarly, we found that BPDCNs with ZRSR2 mutation or loss had increased IR compared to those without spliceosome mutations (Figure 4a).…”

Section: Unique Transcriptomic Features Of Spliceosome Mutated Bpdcnsupporting

confidence: 72%

“…In contrast, ZRSR2 is uniquely necessary for proper splicing of U12 introns (0.3% of human introns), an evolutionarily conserved genomic feature with distinct branch and splice-site sequences [27,28]. In MDS, ZRSR2 mutations promote aberrant IR with a bias toward retention of U12-type introns [29]. Similarly, we found that BPDCNs with ZRSR2 mutation or loss had increased IR compared to those without spliceosome mutations (Figure 4a).…”

Section: Unique Transcriptomic Features Of Spliceosome Mutated Bpdcnmentioning

confidence: 60%

“…Both U2-and U12-type introns were affected, but IR was markedly weighted towards U12-type introns in BPDCNs with ZRSR2 mutation (Figure 4b). We also detected some of the stereotypical mis-splicing patterns associated with specific splicing factor mutations in other cancers [29]. These included preferential exon inclusion or exclusion related to CCNG/GGNG exonic splicing enhancer motifs in cases with SRSF2 mutation [30] and alternative 3' splice sites usage with SF3B1 mutation ( Supplementary Figure 3a-b) [31].…”

Section: Unique Transcriptomic Features Of Spliceosome Mutated Bpdcnmentioning

confidence: 79%

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Sex-biasedZRSR2mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis

Togami

Chung

Madan

et al. 2020

Preprint

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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDCs). BPDCN occurs at least three times more frequently in men than women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation.

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“…introns [29]. Similarly, we found that BPDCNs with ZRSR2 mutation or loss had increased IR compared to those without spliceosome mutations (Figure 4a).…”

Section: Unique Transcriptomic Features Of Spliceosome Mutated Bpdcnsupporting

confidence: 72%

Section: Unique Transcriptomic Features Of Spliceosome Mutated Bpdcnmentioning

confidence: 60%

Section: Unique Transcriptomic Features Of Spliceosome Mutated Bpdcnmentioning

confidence: 79%

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Sex-biasedZRSR2mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis

Togami

Chung

Madan

et al. 2020

Preprint

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“…LUC7L2 mutations have been associated with shorter survival in patients with -7/del7q compared to patients with normal LUC7L2 expression [44,45]. LUCL7L2 has been found aberrantly spliced in MDS cases harboring SRSF2 small deletions [46]. Very rare mutations (<1%) have been found in other SF genes including SF3A1, SF1, PRPF40B, and U2AF2 [5,47].…”

Section: Other Splicing Factor Mutationsmentioning

confidence: 99%

Mutations in Splicing Factor Genes in Myeloid Malignancies: Significance and Impact on Clinical Features

Visconte

Nakashima

Rogers

2019

Cancers

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Components of the pre-messenger RNA splicing machinery are frequently mutated in myeloid malignancies. Mutations in LUC7L2, PRPF8, SF3B1, SRSF2, U2AF1, and ZRSR2 genes occur at various frequencies ranging between 40% and 85% in different subtypes of myelodysplastic syndrome (MDS) and 5% and 10% of acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs). In some instances, splicing factor (SF) mutations have provided diagnostic utility and information on clinical outcomes as exemplified by SF3B1 mutations associated with increased ring sideroblasts (RS) in MDS-RS or MDS/MPN-RS with thrombocytosis. SF3B1 mutations are associated with better survival outcomes, while SRSF2 mutations are associated with a shorter survival time and increased AML progression, and U2AF1 mutations with a lower remission rate and shorter survival time. Beside the presence of mutations, transcriptomics technologies have shown that one third of genes in AML patients are differentially expressed, leading to altered transcript stability, interruption of protein function, and improper translation compared to those of healthy individuals. The detection of SF mutations demonstrates the importance of splicing abnormalities in the hematopoiesis of MDS and AML patients given the fact that abnormal splicing regulates the function of several transcriptional factors (PU.1, RUNX1, etc.) crucial in hematopoietic function. This review provides a summary of the significance of the most frequently mutated SF genes in myeloid malignancies and an update on novel targeted therapies in experimental and clinical trial stages.

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“…Accordingly, in recent years, it has become clear that altering the function of DUB affects HSC homeostasis and may contribute to the onset of MDS and AML (Figure 4) by several mechanisms [254], as described for the DUBs BAP1, a tumor suppressor that cooperates with the polycomb group protein ASXL1 [255][256][257] or A20 [258,259], BRCC3 [260][261][262], USP7 [263,264], and USP10 [265]. DUB gene rearrangements have been reported in pediatric AML [266][267][268] and mis-splicing of USP9X-and its closely related protease USP24-was detected in SRSF2 mutant MDS samples [269]. Finally, consistently with a crucial role of DDR in HSC self-renewal [193,199,270], an increasing number of DUBs impacting on DDR have been implicated in HSC maintenance [271].…”

Section: Deubiquitinating Enzymes In Hscs Genome Stabilitymentioning

confidence: 96%

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Barabino

Citterio

2021

Cancers

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Myeloid neoplasms encompass a very heterogeneous family of diseases characterized by the failure of the molecular mechanisms that ensure a balanced equilibrium between hematopoietic stem cells (HSCs) self-renewal and the proper production of differentiated cells. The origin of the driver mutations leading to preleukemia can be traced back to HSC/progenitor cells. Many properties typical to normal HSCs are exploited by leukemic stem cells (LSCs) to their advantage, leading to the emergence of a clonal population that can eventually progress to leukemia with variable latency and evolution. In fact, different subclones might in turn develop from the original malignant clone through accumulation of additional mutations, increasing their competitive fitness. This process ultimately leads to a complex cancer architecture where a mosaic of cellular clones—each carrying a unique set of mutations—coexists. The repertoire of genes whose mutations contribute to the progression toward leukemogenesis is broad. It encompasses genes involved in different cellular processes, including transcriptional regulation, epigenetics (DNA and histones modifications), DNA damage signaling and repair, chromosome segregation and replication (cohesin complex), RNA splicing, and signal transduction. Among these many players, transcription factors, RNA splicing proteins, and deubiquitinating enzymes are emerging as potential targets for therapeutic intervention.

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Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes

Cited by 16 publications

References 57 publications

Sex-biasedZRSR2mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis

Sex-biasedZRSR2mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis

Mutations in Splicing Factor Genes in Myeloid Malignancies: Significance and Impact on Clinical Features

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

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