- Open Access
SRSF2 mutations in myelodysplasia/myeloproliferative neoplasms
Biomarker Research volume 6, Article number: 29 (2018)
Recurrent gene mutations have been described with varying frequencies in myelodysplasia (MDS) /myeloproliferative neoplasm (MPN) overlap syndromes (MMOS). Recent work has placed significant focus on understanding the role of gene lesions involving the spliceosomal machinery in leukemogeneis. SRSF2 is a gene encoding critical spliceosomal proteins. SRSF2 mutations appear to play an important role in pathogenesis of MMOS, particularly in chronic myelomonocytic leukemia. Inhibition of splicing may be a new therapeutic approach. E7107, a spliceosome inhibitor, has been shown to differentially inhibit splicing more in SRSF2-mutant cells leading to decreased leukemia burden in mice. H3B-8800 is a small molecule modulator of spliceosome complex and has been shown to lower leukemia burden in SRSF2-P95H mutant mice. This review focuses on the incidence of mutant SRSF2 across various MMOS as well as recent clinical development of spliceosome inhibitors.
Myelodysplastic and myeloproliferative overlap syndromes (MMOS) were initially recognized as a unique entity in the third edition of WHO classification of myeloid neoplasms . This group initially had three disorders - chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia, BCR-ABL1− (aCML), and juvenile myelomonocytic leukemia (JMML). The fourth entity, MDS/MPN with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T, previously known as RARS-T), was added in the 2016 revision of WHO classification . Currently, MMOS also includes a fifth group, MDS/MPN unclassifiable, which is inclusive of all other MDS/MPN -like syndromes that do not meet diagnostic criteria for the above.
With the increasing use of next-gene sequencing and molecular studies in clinical practice, new patterns of gene mutations are being reported in myeloid neoplasms [3,4,5,6,7,8]. These mutations are being used as biomarkers for classification and druggable targets [9,10,11,12]. A variety of small molecules including ruxolitinib, enasidenib, midostaurin, and AG-120 are in clinical applications and/or late-stage clinical development [13,14,15,16,17,18,19,20,21].
MDS/MPN overlap syndromes can present with overlapping clinical and morphological features of both MDS (peripheral cytopenia and/or dysplastic bone marrow) and clonal proliferation (leukocytosis, thrombocytosis or organomegaly) during the initial diagnosis . Genomic aberrations have been reported at a frequency as high as 75% along with multiple somatic mutations . Most common mutations reported are TET2, ASXL1 and/or SRSF2 in CMML, NRAS/KRAS in JMML, SETBP1 in aCML and JAK-STAT and/or SF3B1 in MDS/MPN-RS-T [24,25,26,27]. This review focuses on SRSF2 mutations across various entities of MMOS.
SRSF2 (Serine and arginine Rich Splicing Factor 2), also called SC35 and SRp30b, belongs to the SR (Serine and Arginine rich) protein family [28, 29]. It was recognized first in 1990 by Fu and Maniatis using a monocloncal antibody developed against mammalian spliceosomes . It was reported to play a role in splicing during spliceosome assembly [31, 32]. SRSF2 has a RNA recognition motif and thus promotes spliceosome assembly at adjacent splice sites to allow appropriate exon inclusion [28, 33, 34]. In addition, SRSF2 was reported to play an active role in transcription elongation and in coupling transcription and splicing processes [35, 36].
SRSF2 in oncogenesis
The oncogenic potential of SRSF2 was first demonstrated in SRSF2 knock-out mouse embryo fibroblasts (MEFs). SRSF2 mutation increased double-strand DNA breaks, p53 hyperphosphorylation and hyperacetylation with cell cycle arrest . Similar findings were also duplicated in mouse hematopoietic cells, with growth arrest, early senescence and apoptosis in SRSF2 deleted cells . In another study based on similar intervention, SRSF2 homozygous knockout mice showed 70–90% loss of thymocytes with significantly increased CD4-/CD8- T cells and decreased CD4+/CD8+ T cells. Thus, loss of SRSF2 seemed to affect T cell maturation in thymus, possibly secondary to altered splicing of CD45 as reported in the study .
While loss of SRSF2 led to decreased survival, mutant SRSF2 (SRSF2-mut) expression was associated with oncogenesis. Direct association of SRSF2 in development of myelodysplasia was demonstrated in SRSF2-P95H mutant mice . P95H is the most common mutation site in the SRSF2 gene [41,42,43,44,45] and its proximity to RRM site of SRSF2 might play a role in altering RNA binding abilities  . Heterozygous P95H mutant and homozygous SRSF2 deleted bone marrow mononuclear cells led to development of significant leukopenia and anemia in lethally irradiated recipient mice. However, only P95H mutated mice developed macrocytic RBCs and had normal bone marrow cellularity in contrast to bone marrow aplasia seen with homozygous SRSF2 deletion. Peripheral erythroid and myeloid dysplasia was also seen only with P95H mutant mice . These findings correlate with MDS findings in humans.
SRSF2 mutant cells have been shown to require wild-type (WT) SRSF2 allele for the cell survival, explaining the phenotypic differences between heterozygous and homozygous genotypes . Hemizygous SRSF2P95H/−mice had shorter survival with severe bone marrow aplasia in contrast to SRSF2P95H/+ mice (p = 0.004). Hemizygous cells also showed two-fold higher mis-splicing events compared to heterozygous cells . Similar oncogenic associations secondary to mis-splicing have also been reported with other splicing factor mutations such as U2AF1 and SF3B1  [50, 51]. SRSF2 mutation frequently occurs in close association with these and other mutations [26, 42, 44]. During disease progression of MDS, additional mutations are acquired .
SRSF2 in MDS/MPN overlap syndromes
In 2011, Yoshida et al. identified frequently recurring splicing factor mutations in a cohort of adult patients with myeloid neoplasms through performing whole-exome sequencing. SF3B1 (36%) was the most common mutation followed by SRSF2 (25.6%), U2AF35 (16.9%) and ZRSR2 (10.5%) . These mutations were more frequent and comparatively more specific to the diseases with myelodysplastic features (MDS, CMML, t-AML and AML-MRC) . SRSF2 mutation was reported with a high frequency of 28–47% [41,42,43, 53] in other cohorts of CMML patients and was reported to be significantly associated with higher age, higher hemoglobin, normal karyotype and TET2 mutation [26, 45, 54]. Interestingly, it occurred mutually exclusively with EZH2 mutation [42, 44]. No significant association had been reported with leukocytosis, blast percentage, WHO histologic categories (CMML-1 and CMML-2) or cytogenetic risk categories. No specific morphological or immunohistochemical features in the bone marrow (e.g. dysplasia, CD14 and CD34 positive cells) were significantly associated with SRSF2 mutations in a study done on MDS/MPN entities. SRSF2 testing on bone marrow specimens was shown to be 44.4% sensitive and 88.1% specific in diagnosing CMML over MDS or MPN; with modest positive likelihood ratio of 3.73 .
SRSF2 has been associated with worse survival outcomes in low-risk MDS patients and PMF [43, 44, 55] but evidence has not been very clear among MDS/MPN overlap syndromes. Earlier studies investigating SRSF2 mutations in MDS/MPN overlap syndromes reported no influence of SRSF2-mut on overall survival (OS) either in CMML or other MDS/MPN overlap syndromes [26, 42, 56]. The only impact SRSF2-mut had on survival was noted by Meggendorfer et al. analyzing a series of CMML patients. Patients co-harboring RUNX1 and SRSF2 mutations appeared to have improved OS compared to those who possessed wild-type (WT) variants.
An international cohort study showed poor OS outcomes associated with the SRSF2 mutations in CMML patients aged ≤65 years but with non-significant difference among leukemic transformation rates . Similar outcomes with decreased OS along with decreased progression free survival (PFS) or leukemia free survival (LFS) were also reported in two studies that enrolled 56 and 312 CMML patients, respectively [27, 58]. Additional factors that negatively influenced OS as per multivariate analyses were older age (> 65 years, p = 0.04), WBC > 15 × 109/L (p < 0.0001), presence of anemia (hemoglobin < 10 g/dL in women and < 11 g/dL in men; p = 0.0002), thrombocytopenia (< 100 × 109/L; p < 0.0001) and an absolute lymphocyte count (ALC) > 4 × 109/L (p = 0.03) [27, 56]. Genotypically, ASXL1 was the only mutation which predicted inferior OS and LFS in multivariate analyses.
Multiple prognostic models based on phenotypic and cytogenetic characteristics have been developed for CMML. These include the MD Anderson Prognostic Score (MDAPS) , the Spanish Cytogenetic Risk Stratification  and the CMML Prognostic Scoring System (CPSS) . The MDAPS and the CPSS were dependent on clinical factors and/or basic laboratory findings. The CPSS also incorporated the Genetic Risk Score as determined by the Spanish risk stratification. More recently, attempts have been made to incorporate ASXL1 mutation status into these models based on previous data regarding impact on survival. Recently, two more prognostic models were proposed; the Groupe Francophone des Myelodysplasies (GFM) model  and the Mayo molecular model . Of note, the GFM model was validated in a separate cohort of 165 patients with a median follow up of 27.3 months .
The CPSS was also updated to incorporate the impact of multiple mutations including ASXL1, NRAS, RUNX1 and SETBP1. The updated system, named CPSS-Mol, assigned variable scores to different mutations as well as the cytogenetic abnormalities . A composite score was then determined using phenotypic variables as defined by CPSS and the “Genetic Risk Group”. Four risk categories were delineated and the scoring system was validated in a separate cohort of 286 patients. Lastly, prognostic implications of different types of missense mutations occurring at the P95 site of SRSF2 gene have also been reported; the P95H variant being reported to have better outcomes compared to P95L or P95A . Table 1 summarizes the various studies evaluating SRSF2 mutation frequency and reported impact on overall and progression free survival in CMML.
Among a cohort of 371 children, SRSF2 mutation was only seen in 2 patients and both with normal karyotype along with co-existing RAS mutations . Both patients received HSCT in the study. One relapsed with loss of SRSF2 mutation at relapse; while RAS mutation persisted. In two other studies, only 1/76 patients with JMML carried a SRSF2 mutation [26, 65]. This mutation had not been described previously and was reported as in-frame deletion in contrast to mis-sense mutations seen in adults. Although morphologically similar, genotypic characteristics of JMML are distinct from those of CMML with RAS, PTPN11, NFI and CBL. Rarity of splicing factor mutations in JMML and their loss at progression of disease likely precludes their independent role in its pathogenesis. The frequency of SRSF2 mutations in JMML was summarized in Table 2.
Atypical CML, BCR-ABL1 −
Atypical CML (aCML) is a rare entity among MDS/MPN overlap syndromes characterized by the absence of the BCR-ABL1 fusion gene as well as rearrangements of the PDGFRA, PDGFRB or FGFR1 genes . ASXL1 (20–70%), SETBP1 (25–30%) and TET2 (43%) mutations are the most common mutations detected in aCML [66, 67]. SETBP1 mutations correlate with worse survival outcomes . A high frequency of SRSF2 mutations (40%) was reported among a cohort of 60 aCML  while its frequency has been reported variably in other studies [67, 69, 70]. SRSF2 mutation appears more frequently with ASXL1-mut (p = 0.01) and SETBP1-mut (p = 0.004) compared to WT.
This entity was previously known as refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T) and defined under the MDS/MPN-U umbrella diagnosis. This disease has now been accepted as a separate entity in 2016 revision of WHO classification . Splicing factor mutations are common in this group, with SF3B1 being the most frequently occurring mutation (85–91%) [67, 71, 72]. SF3B1 mutation status is strongly associated with increased number of ringed sideroblasts (p = 0.006). JAK2 (33–59%), TET2 (10–31%) and ASXL1 (20–29%) are the other frequently occurring mutations in this entity. SRSF2 is comparatively less common (2–9%) and is mostly present in association with other mutations in genotypes carrying high mutation burden . In a cohort of 75 patients, SRSF2 was present in 5 cases and all of them carried ≥4 mutations , suggesting that it is less likely to play a driver mutation role in this entity (Table 2).
MDS/MPN – Unclassifiable
MDS/MPN-U is another rare entity with heterogenous dysplastic and proliferative features except some distinct associations such as isolated trisomy 8 seen in about 15% of cases compared to MDS (5%) and MPN (4%) . JAK2 mutation is one of the most common (23–66%) mutations reported in this group  but has not been reported to have prognostic importance. Other mutations occur in comparable frequencies, ASXL1 and TET2 (36%), U2AF1 (18%), SRSF2 (15%) and SF3B1 (13%). Overall, MDS/MPN-U presents a mixed picture as opposed to other MMOS. Thrombocytosis has been associated with improved survival in this group  but role of SRSF2 in pathogenesis or as prognostic indicator has not been well defined yet (Table 2).
Therapeutic implications of SRSF2
Aberrant spliceosome function secondary to mutated SRSF2 has been associated with mis-splicing of multiple genes (e.g. EZH2, RUNX1, BCOR, IKAROS and CASP8, etc.) that are implicated in pathogenesis of myeloid neoplasms [40, 43]. Inhibition of splicing has been analyzed as possible therapeutic target. E7107, a spliceosome inhibitor, has shown to differentially inhibit splicing more in SRSF2-mut cells leading to decreased leukemia burden in mice . A phase 1 clinical trial investigating E7107 in metastatic or locally advanced solid tumors was discontinued prematurely due to vision loss reported as adverse event in 2 cases . A parallel phase I trial conducted in Europe also reported one instance of grade 4 visual disturbance secondary to optic neuritis which improved after treatment with steroids. Nevertheless, the study was discontinued for safety concerns .
Another compound, H3B-8800, acts as a modulator of the SF3b complex. It has demonstrated a preferential cytotoxic effect on SF3B1-mutant cells secondary to GC-rich intronic retention . Decreased leukemic burden was reported in SRSF2-P95H mutant mice compared to SRSF2-WT variants. A phase I clinical trial (NCT02841540) is underway to evaluate safety of this compound in patients with MDS, AML and CMML.
SRSF2 is a frequent mutation seen in MDS/MPN overlap syndromes, especially CMML. It has been shown to play a multi-faceted role during the oncogenesis of these disorders influencing transcription, splicing, translation and genomic stability. There is insufficient evidence to establish it as a primary driver mutation. Conflicting data on its prognostic role especially in CMML demand further evaluation to differentiate worse prognostic outcomes due to presence of SRSF2 mutation as opposed to other factors (e.g. presence of increased mutation burden). Targeting mis-splicing events secondary to splicing factor mutations with novel spliceosome inhibitors is an exciting approach with multiple possible therapeutic implications.
atypical Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Juvenile Myelomonocytic Leukemia
Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100(7):2292–302.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.
Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373(12):1136–52.
Hwang SM, Kim SY, Kim JA, Park H-S, Park SN, Im K, Kim K, Kim S-M, Lee DS. Short telomere length and its correlation with gene mutations in myelodysplastic syndrome. J Hematol Oncol. 2016;9(1):62.
Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, Aziz A, Godfrey AL, Hinton J, Martincorena I, Van Loo P, Jones AV, Guglielmelli P, Tarpey P, Harding HP, Fitzpatrick JD, Goudie CT, Ortmann CA, Loughran SJ, Raine K, Jones DR, Butler AP, Teague JW, O'Meara S, McLaren S, Bianchi M, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405.
Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, Yoon CJ, Ellis P, Wedge DC, Pellagatti A, Shlien A, Groves MJ, Forbes SA, Raine K, Hinton J, Mudie LJ, McLaren S, Hardy C, Latimer C, Della Porta MG, O'Meara S, Ambaglio I, Galli A, Butler AP, Walldin G, Teague JW, Quek L, Sternberg A, Gambacorti-Passerini C, Cross NC, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616–27.
Tirado CA, Siangchin K, Shabsovich DS, Sharifian M, Schiller G. A novel three-way rearrangement involving ETV6 (12p13) and ABL1 (9q34) with an unknown partner on 3p25 resulting in a possible ETV6-ABL1 fusion in a patient with acute myeloid leukemia: a case report and a review of the literature. Biomarker Research. 2016;4(1):16.
Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, Shih LY, Haferlach T, Chiba S, Nakauchi H, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478(7367):64–9.
Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how? Hematology Am Soc Hematol Educ Program. 2014;2014(1):277–86.
Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, Potter NE, Heuser M, Thol F, Bolli N, Gundem G, Van Loo P, Martincorena I, Ganly P, Mudie L, McLaren S, O’Meara S, Raine K, Jones DR, Teague JW, Butler AP, Greaves MF, Ganser A, Döhner K, Schlenk RF, Döhner H, Campbell PJ. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21.
Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909–18.
Welch JS, Petti AA, Miller CA, Fronick CC, O’Laughlin M, Fulton RS, Wilson RK, Baty JD, Duncavage EJ, Tandon B, Lee Y-S, Wartman LD, Uy GL, Ghobadi A, Tomasson MH, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Cashen AF, Schroeder MA, Jacoby MA, Heath SE, Luber K, Janke MR, Hantel A, Khan N, et al. TP53 and Decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375(21):2023–36.
Amatangelo MD, Quek L, Shih A, Stein EM, Roshal M, David MD, Marteyn B, Farnoud NR, de Botton S, Bernard OA, Wu B, Yen KE, Tallman MS, Papaemmanuil E, Penard-Lacronique V, Thakurta A, Vyas P, Levine RL. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130(6):732–41.
Maffini E, Giaccone L, Festuccia M, Brunello L, Buondonno I, Ferrero D, Boccadoro M, Dellacasa C, Busca A, Novero D, Bruno B. Ruxolitinib in steroid refractory graft-vs.-host disease: a case report. J Hematol Oncol. 2016;9(1):67.
Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, Stone RM, DeAngelo DJ, Levine RL, Flinn IW, Kantarjian HM, Collins R, Patel MR, Frankel AE, Stein A, Sekeres MA, Swords RT, Medeiros BC, Willekens C, Vyas P, Tosolini A, Xu Q, Knight RD, Yen KE, Agresta S, de Botton S, Tallman MS. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722–31.
Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Dohner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Dohner H. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454–64.
Verstovsek S, Odenike O, Singer JW, Granston T, Al-Fayoumi S, Deeg HJ. Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies. J Hematol Oncol. 2016;9(1):137.
Yacoub A, Prochaska L. Ruxolitinib improves symptoms and quality of life in a patient with systemic mastocytosis. Biomarker Research. 2016;4(1):2.
Saygin C, Carraway HE. Emerging therapies for acute myeloid leukemia. J Hematol Oncol. 2017;10(1):93.
Verstovsek S, Gotlib J, Mesa RA, Vannucchi AM, Kiladjian J-J, Cervantes F, Harrison CN, Paquette R, Sun W, Naim A, Langmuir P, Dong T, Gopalakrishna P, Gupta V. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156.
Verstovsek S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, Deininger MWN, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH, Arcasoy MO, Hexner EO, Lyons RM, Paquette R, Raza A, Jones M, Kornacki D, Sun K, Kantarjian H. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55.
Orazi A, Germing U. The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia. 2008;22(7):1308–19.
Tiu RV, Gondek LP, O'Keefe CL, Elson P, Huh J, Mohamedali A, Kulasekararaj A, Advani AS, Paquette R, List AF, Sekeres MA, McDevitt MA, Mufti GJ, Maciejewski JP. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood. 2011;117(17):4552–60.
Mughal TI, Cross NC, Padron E, Tiu RV, Savona M, Malcovati L, Tibes R, Komrokji RS, Kiladjian JJ, Garcia-Manero G, Orazi A, Mesa R, Maciejewski JP, Fenaux P, Itzykson R, Mufti G, Solary E, List AF. An international MDS/MPN working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms. Haematologica. 2015;100(9):1117–30.
Reiter A, Invernizzi R, Cross NC, Cazzola M. Molecular basis of myelodysplastic/myeloproliferative neoplasms. Haematologica. 2009;94(12):1634–8.
Kar SA, Jankowska A, Makishima H, Visconte V, Jerez A, Sugimoto Y, Muramatsu H, Traina F, Afable M, Guinta K, Tiu RV, Przychodzen B, Sakaguchi H, Kojima S, Sekeres MA, List AF, McDevitt MA, Maciejewski JP. Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia. Haematologica. 2013;98(1):107–13.
Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M, Berthon C, Ades L, Fenaux P, Beyne-Rauzy O, Vey N, Braun T, Haferlach T, Dreyfus F, Cross NC, Preudhomme C, Bernard OA, Fontenay M, Vainchenker W, Schnittger S, Birnbaum D, Droin N, Solary E. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013;31(19):2428–36.
Kielkopf CL. Insights from structures of cancer-relevant pre-mRNA splicing factors. Curr Opin Genet Dev. 2018;48:57–66.
Fu XD, Maniatis T. Isolation of a complementary DNA that encodes the mammalian splicing factor SC35. Science. 1992;256(5056):535–8.
Fu XD, Maniatis T. Factor required for mammalian spliceosome assembly is localized to discrete regions in the nucleus. Nature. 1990;343(6257):437–41.
Fu XD, Maniatis T. The 35-kDa mammalian splicing factor SC35 mediates specific interactions between U1 and U2 small nuclear ribonucleoprotein particles at the 3′ splice site. Proc Natl Acad Sci U S A. 1992;89(5):1725–9.
Wahl MC, Will CL, Luhrmann R. The spliceosome: design principles of a dynamic RNP machine. Cell. 2009;136(4):701–18.
Liu HX, Chew SL, Cartegni L, Zhang MQ, Krainer AR. Exonic splicing enhancer motif recognized by human SC35 under splicing conditions. Mol Cell Biol. 2000;20(3):1063–71.
Howard JM, Sanford JR. The RNAissance family: SR proteins as multifaceted regulators of gene expression. Wiley Interdiscip Rev RNA. 2015;6(1):93–110.
Lin S, Coutinho-Mansfield G, Wang D, Pandit S, Fu XD. The splicing factor SC35 has an active role in transcriptional elongation. Nat Struct Mol Biol. 2008;15(8):819–26.
Das R, Yu J, Zhang Z, Gygi MP, Krainer AR, Gygi SP, Reed R. SR proteins function in coupling RNAP II transcription to pre-mRNA splicing. Mol Cell. 2007;26(6):867–81.
Xiao R, Sun Y, Ding JH, Lin S, Rose DW, Rosenfeld MG, Fu XD, Li X. Splicing regulator SC35 is essential for genomic stability and cell proliferation during mammalian organogenesis. Mol Cell Biol. 2007;27(15):5393–402.
Komeno Y, Huang YJ, Qiu J, Lin L, Xu Y, Zhou Y, Chen L, Monterroza DD, Li H, DeKelver RC, Yan M, Fu XD, Zhang DE. SRSF2 is essential for hematopoiesis, and its myelodysplastic syndrome-related mutations dysregulate alternative pre-mRNA splicing. Mol Cell Biol. 2015;35(17):3071–82.
Wang HY, Xu X, Ding JH, Bermingham JR Jr, Fu XD. SC35 plays a role in T cell development and alternative splicing of CD45. Mol Cell. 2001;7(2):331–42.
Kim E, Ilagan JO, Liang Y, Daubner GM, Lee SC, Ramakrishnan A, Li Y, Chung YR, Micol JB, Murphy ME, Cho H, Kim MK, Zebari AS, Aumann S, Park CY, Buonamici S, Smith PG, Deeg HJ, Lobry C, Aifantis I, Modis Y, Allain FH, Halene S, Bradley RK, Abdel-Wahab O. SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell. 2015;27(5):617–30.
Patnaik MM, Lasho TL, Finke CM, Hanson CA, Hodnefield JM, Knudson RA, Ketterling RP, Pardanani A, Tefferi A. Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance. Am J Hematol. 2013;88(3):201–6.
Meggendorfer M, Roller A, Haferlach T, Eder C, Dicker F, Grossmann V, Kohlmann A, Alpermann T, Yoshida K, Ogawa S, Koeffler HP, Kern W, Haferlach C, Schnittger S. SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood. 2012;120(15):3080–8.
Makishima H, Visconte V, Sakaguchi H, Jankowska AM, Abu Kar S, Jerez A, Przychodzen B, Bupathi M, Guinta K, Afable MG, Sekeres MA, Padgett RA, Tiu RV, Maciejewski JP. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood. 2012;119(14):3203–10.
Wu SJ, Kuo YY, Hou HA, Li LY, Tseng MH, Huang CF, Lee FY, Liu MC, Liu CW, Lin CT, Chen CY, Chou WC, Yao M, Huang SY, Ko BS, Tang JL, Tsay W, Tien HF. The clinical implication of SRSF2 mutation in patients with myelodysplastic syndrome and its stability during disease evolution. Blood. 2012;120(15):3106–11.
Federmann B, Abele M, Rosero Cuesta DS, Vogel W, Boiocchi L, Kanz L, Quintanilla-Martinez L, Orazi A, Bonzheim I, Fend F. The detection of SRSF2 mutations in routinely processed bone marrow biopsies is useful in the diagnosis of chronic myelomonocytic leukemia. Hum Pathol. 2014;45(12):2471–9.
Daubner GM, Clery A, Jayne S, Stevenin J, Allain FH. A syn-anti conformational difference allows SRSF2 to recognize guanines and cytosines equally well. EMBO J. 2012;31(1):162–74.
Lee SC, Dvinge H, Kim E, Cho H, Micol JB, Chung YR, Durham BH, Yoshimi A, Kim YJ, Thomas M, Lobry C, Chen CW, Pastore A, Taylor J, Wang X, Krivtsov A, Armstrong SA, Palacino J, Buonamici S, Smith PG, Bradley RK, Abdel-Wahab O. Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nat Med. 2016;22(6):672–8.
Hou HA, Kuo YY, Tang JL, Chou WC, Yao M, Lai YJ, Lin CC, Chen CY, Liu CY, Tseng MH, Huang CF, Chiang YC, Lee FY, Liu MC, Liu CW, Huang SY, Ko BS, Wu SJ, Tsay W, Chen YC, Tien HF. Clinical implications of the SETBP1 mutation in patients with primary myelodysplastic syndrome and its stability during disease progression. Am J Hematol. 2014;89(2):181–6.
Yip BH, Steeples V, Repapi E, Armstrong RN, Llorian M, Roy S, Shaw J, Dolatshad H, Taylor S, Verma A, Bartenstein M, Vyas P, Cross NC, Malcovati L, Cazzola M, Hellstrom-Lindberg E, Ogawa S, Smith CW, Pellagatti A, Boultwood J. The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes. J Clin Invest. 2017;127(6):2206–21.
Dolatshad H, Pellagatti A, Fernandez-Mercado M, Yip BH, Malcovati L, Attwood M, Przychodzen B, Sahgal N, Kanapin AA, Lockstone H, Scifo L, Vandenberghe P, Papaemmanuil E, Smith CW, Campbell PJ, Ogawa S, Maciejewski JP, Cazzola M, Savage KI, Boultwood J. Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. Leukemia. 2015;29(8):1798.
Mortera-Blanco T, Dimitriou M, Woll PS, Karimi M, Elvarsdottir E, Conte S, Tobiasson M, Jansson M, Douagi I, Moarii M, Saft L, Papaemmanuil E, Jacobsen SEW, Hellstrom-Lindberg E. SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells. Blood. 2017;130(7):881–90.
Patnaik MM, Wassie EA, Lasho TL, Hanson CA, Ketterling R, Tefferi A. Blast transformation in chronic myelomonocytic leukemia: risk factors, genetic features, survival, and treatment outcome. Am J Hematol. 2015;90(5):411–6.
Wassie EA, Itzykson R, Lasho TL, Kosmider O, Finke CM, Hanson CA, Ketterling RP, Solary E, Tefferi A, Patnaik MM. Molecular and prognostic correlates of cytogenetic abnormalities in chronic myelomonocytic leukemia: a Mayo Clinic-French consortium study. Am J Hematol. 2014;89(12):1111–5.
Meggendorfer M, Haferlach T, Alpermann T, Jeromin S, Haferlach C, Kern W, Schnittger S. Specific molecular mutation patterns delineate chronic neutrophilic leukemia, atypical chronic myeloid leukemia, and chronic myelomonocytic leukemia. Haematologica. 2014;99(12):e244–6.
Lasho TL, Jimma T, Finke CM, Patnaik M, Hanson CA, Ketterling RP, Pardanani A, Tefferi A. SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival. Blood. 2012;120(20):4168–71.
Patnaik MM, Padron E, LaBorde RR, Lasho TL, Finke CM, Hanson CA, Hodnefield JM, Knudson RA, Ketterling RP, Al-kali A, Pardanani A, Ali NA, Komrokji RS, Tefferi A. Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia. 2013;27(7):1504–10.
Patnaik MM, Wassie EA, Padron E, Onida F, Itzykson R, Lasho TL, Kosmider O, Finke CM, Hanson CA, Ketterling RP, Komrokji R, Tefferi A, Solary E. Chronic myelomonocytic leukemia in younger patients: molecular and cytogenetic predictors of survival and treatment outcome. Blood Cancer J. 2015;5:e270.
Ouyang Y, Qiao C, Chen Y, Zhang SJ. Clinical significance of CSF3R, SRSF2 and SETBP1 mutations in chronic neutrophilic leukemia and chronic myelomonocytic leukemia. Oncotarget. 2017;8(13):20834–41.
Onida F, Kantarjian HM, Smith TL, Ball G, Keating MJ, Estey EH, Glassman AB, Albitar M, Kwari MI, Beran M. Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood. 2002;99(3):840–9.
Such E, Cervera J, Costa D, Sole F, Vallespi T, Luno E, Collado R, Calasanz MJ, Hernandez-Rivas JM, Cigudosa JC, Nomdedeu B, Mallo M, Carbonell F, Bueno J, Ardanaz MT, Ramos F, Tormo M, Sancho-Tello R, del Canizo C, Gomez V, Marco V, Xicoy B, Bonanad S, Pedro C, Bernal T, Sanz GF. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica. 2011;96(3):375–83.
Such E, Germing U, Malcovati L, Cervera J, Kuendgen A, Della Porta MG, Nomdedeu B, Arenillas L, Luno E, Xicoy B, Amigo ML, Valcarcel D, Nachtkamp K, Ambaglio I, Hildebrandt B, Lorenzo I, Cazzola M, Sanz G. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood. 2013;121(15):3005–15.
Patnaik MM, Itzykson R, Lasho TL, Kosmider O, Finke CM, Hanson CA, Knudson RA, Ketterling RP, Tefferi A, Solary E. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia. 2014;28(11):2206–12.
Elena C, Galli A, Such E, Meggendorfer M, Germing U, Rizzo E, Cervera J, Molteni E, Fasan A, Schuler E, Ambaglio I, Lopez-Pavia M, Zibellini S, Kuendgen A, Travaglino E, Sancho-Tello R, Catricala S, Vicente AI, Haferlach T, Haferlach C, Sanz GF, Malcovati L, Cazzola M. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood. 2016;128(10):1408–17.
Hirabayashi S, Flotho C, Moetter J, Heuser M, Hasle H, Gruhn B, Klingebiel T, Thol F, Schlegelberger B, Baumann I, Strahm B, Stary J, Locatelli F, Zecca M, Bergstraesser E, Dworzak M, Van den Heuvel-Eibrink MM, De Moerloose B, Ogawa S, Niemeyer CM, Wlodarski MW, European working group of MDSiC. Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML. Blood. 2012;119(11):e96–9.
Takita J, Yoshida K, Sanada M, Nishimura R, Okubo J, Motomura A, Hiwatari M, Oki K, Igarashi T, Hayashi Y, Ogawa S. Novel splicing-factor mutations in juvenile myelomonocytic leukemia. Leukemia. 2012;26(8):1879–81.
Li B, Gale RP, Xiao Z. Molecular genetics of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia. J Hematol Oncol. 2014;7:93.
Meggendorfer M, Jeromin S, Haferlach C, Kern W, Haferlach T. The mutational landscape of 18 investigated genes clearly separates four subtypes of myelodysplastic/myeloproliferative neoplasms. Haematologica. 2018;103(5):e192–5.
Linder K, Iragavarapu C, Liu D. SETBP1 mutations as a biomarker for myelodysplasia/myeloproliferative neoplasm overlap syndrome. Biomark Res. 2017;5:33.
Senin A, Arenillas L, Martinez-Aviles L, Fernandez-Rodriguez C, Bellosillo B, Florensa L, Besses C, Alvarez-Larran A. Molecular characterization of atypical chronic myeloid leukemia and chronic neutrophilic leukemia. Med Clin (Barc). 2015;144(11):487–90.
Patnaik MM, Barraco D, Lasho TL, Finke CM, Reichard K, Hoversten KP, Ketterling RP, Gangat N, Tefferi A. Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia. Am J Hematol. 2017;92(6):542–8.
Jeromin S, Haferlach T, Weissmann S, Meggendorfer M, Eder C, Nadarajah N, Alpermann T, Kohlmann A, Kern W, Haferlach C, Schnittger S. Refractory anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in SF3B1 or other spliceosome genes accompanied by JAK2V617F and ASXL1 mutations. Haematologica. 2015;100(4):e125–7.
Patnaik MM, Lasho TL, Finke CM, Hanson CA, King RL, Ketterling RP, Gangat N, Tefferi A. Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) and the role of next-generation sequencing. Am J Hematol. 2016;91(5):492–8.
DiNardo CD, Daver N, Jain N, Pemmaraju N, Bueso-Ramos C, Yin CC, Pierce S, Jabbour E, Cortes JE, Kantarjian HM, Garcia-Manero G, Verstovsek S. Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy. Leukemia. 2014;28(4):958–61.
Hong DS, Kurzrock R, Naing A, Wheler JJ, Falchook GS, Schiffman JS, Faulkner N, Pilat MJ, O'Brien J, LoRusso P. A phase I, open-label, single-arm, dose-escalation study of E7107, a precursor messenger ribonucleic acid (pre-mRNA) splicesome inhibitor administered intravenously on days 1 and 8 every 21 days to patients with solid tumors. Investig New Drugs. 2014;32(3):436–44.
Eskens FA, Ramos FJ, Burger H, O'Brien JP, Piera A, de Jonge MJ, Mizui Y, Wiemer EA, Carreras MJ, Baselga J, Tabernero J. Phase I pharmacokinetic and pharmacodynamic study of the first-in-class spliceosome inhibitor E7107 in patients with advanced solid tumors. Clin Cancer Res. 2013;19(22):6296–304.
Seiler M, Yoshimi A, Darman R, Chan B, Keaney G, Thomas M, Agrawal AA, Caleb B, Csibi A, Sean E, Fekkes P, Karr C, Klimek V, Lai G, Lee L, Kumar P, Lee SC, Liu X, Mackenzie C, Meeske C, Mizui Y, Padron E, Park E, Pazolli E, Peng S, Prajapati S, Taylor J, Teng T, Wang J, Warmuth M, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018;24(4):497–504.
Sun C, Zhang S, Qiao C, Yang X, Li J. Clinical manifestation of the SRSF2 gene mutation in Chinese patients with chronic myelomonocytic leukemia. Chin Med J. 2014;127(24):4215–9.
Alpermann T, Haferlach T, Schrauder C, Konietschke R, Haferlach C, Kern W, Schnittger S. Mutational screening of CSF3R, ASXL1, SETBP1, and SRSF2 in chronic neutrophilic leukemia (CNL), atypical CML and CMML cases. Blood. 2013;122(21):105–5.
The study was partly supported by the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.
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Aujla, A., Linder, K., Iragavarapu, C. et al. SRSF2 mutations in myelodysplasia/myeloproliferative neoplasms. Biomark Res 6, 29 (2018). https://doi.org/10.1186/s40364-018-0142-y