Spliceosome mutations are common in persons with myeloproliferative neoplasm-associated myelofibrosis with RBC-transfusion-dependence and correlate with response to pomalidomide

Chowdhury, Onima; O’Sullivan, Jennifer; Barkas, Nikolaos; Wang, Guanlin; Buck, Gemma; Hamblin, Angela; Tefferi, Ayalew; Al-Ali, Haifa Kathrin; Barosi, Giovanni; Devos, Timothy; Gisslinger, Heinz; Jiang, Qian; Kiladjian, Jean Jacques; Mesa, Ruben A.; Passamonti, Francesco; Ribrag, Vincent; Schiller, Gary J.; Vannucchi, Alessandro M.; Zhou, Daobin; McMullin, Mary Frances; Zhong, Jianhua; Gale, Robert Peter; Mead, Adam J.; Catalano, John; Stevenson, William; Gastl, Günther; Linkesch, Werner; Droogenbroeck, Jan Van; Mineur, Philippe; Gupta, Vikas; Turner, A. Robert; Nevill, Thomas J.; Li, Jianyong; Shen, Zhi-Xiang; Liu, Ting; Bron, Dominique; Natarajan-Amé, Shanti; Récher, Christian; Demory, Jean Loup; Schlenk, Richard F.; Grießhammer, Martin; Cazzola, Mario; Saglio, Giuseppe; Specchia, Giorgina; Pane, Fabrizio; Boekhorst, Peter te; Raymakers, Reinier; Abdulkadyrov, Kudrat; Соколова, М. А.; Salogub, Galina; Zaritskiy, Andrey; Cervantes, Francisco; Boluda, Juan Carlos Hernández; Ojeda, Emilio; Tesfa, Daniel; Nilsson, Lars; Drummond, Mark; Reilly, John T.; Harrison, Claire; Milojković, Dragana; Rivera, Candido E.; Besa, Emmanuel C.; Deeg, H. Joachim; Mascarenhas, John; Prchal, Josef T.; Tiu, Ramon V.; Talpaz, Moshe; Wang, Jen C.; Rampal, Raajit K.; Rondelli, Damiano; McCaul, Kelly; Brown, Randall W.; Komatsu, Norio; Ohyashiki, Kazuma; Ando, Kiyoshi; Kawabata, Hiroshi; Takenaka, Katsuto; Hata, Tomoko; Vardiman, James W.

doi:10.1038/s41375-020-0979-6

Cited by 8 publications

(5 citation statements)

References 13 publications

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“…The efficacy of IMiDs is well established in MM; although not included among standard therapeutic options, IMiDs were explored in MF setting about a decade ago: some retrospective studies in MF patients receiving these agents documented a higher response rate in the presence of mutations involving spliceosome SRSF2, U2AF1, ZRSR2 and SFRB1. 22,23 In this respect, a targeted high-throughput sequencing on PB of our patient, at the time of MF evolution, did not reveal any additional mutation. The IMiDs have demonstrated clinical activity in ameliorating anemia, thrombocytopenia and splenomegaly due to their anti-inflammatory, anti-proliferative and anti-angiogenic effects through inhibition of NF-kB mediated pro-inflammatory and apoptotic circulating cytokines, including IL-2R, IL-6, IL-10, IL-8, TGFβ and TNF-α, which are all significantly increased in MF patients.…”

Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 65%

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Lenalidomide: A double‐edged sword for concomitant multiple myeloma and post‐essential thrombocythemia myelofibrosis

et al. 2021

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Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 65%

Lenalidomide: A double‐edged sword for concomitant multiple myeloma and post‐essential thrombocythemia myelofibrosis

et al. 2021

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“…Heterozygous missense mutations around hotspot S34 and Q157 are described. 1–2 1–2 16 6 Associated with disease progression and reduced overall survival in MF [ 60 , 69 , 118 ] ZRSR2 Protein associates with the U2 auxiliary factor heterodimer, which is required for the recognition of a functional 3ʹ splice site in pre-mRNA splicing. Frameshift/nonsense and missense mutations are described.…”

Section: Mutational Landscape Of Mpnmentioning

confidence: 99%

<p>Impact of Mutational Profile on the Management of Myeloproliferative Neoplasms: A Short Review of the Emerging Data</p>

Loscocco¹,

Guglielmelli²,

Vannucchi³

2020

OTT

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Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by an increased risk of thrombosis and progression to acute myeloid leukemia. MPN are associated with driver mutations in JAK2, CALR and MPL which are crucial for the diagnosis and lead to a constitutive activation of the JAK-STAT signaling, independent of cytokine regulation. Moreover, most patients have concomitant mutations in genes involved in DNA methylation, chromatin modification, messenger RNA splicing, transcription regulation and signal transduction. These additional mutations may arise before, in the context of clonal hematopoiesis of indeterminate potential (CHIP), or after the acquisition of the driver mutation. The clinical phenotype of MPN results from complex interactions between mutations and host factors. The increased application of next-generation sequencing (NGS) techniques to a large series of patients with MPN has expanded the knowledge of mutational landscape and contributed to define the clinical significance of mutations. This molecular information is being increasingly used to refine diagnosis, risk stratification, monitoring of residual disease and response to treatment. ASXL1, SRSF2, EZH2, IDH1/IDH2 and U2AF1 mutations are associated with a more advanced disease and reduced overall survival in primary myelofibrosis (PMF), whereas spliceosome mutations in Polycythemia vera (PV) and essential thrombocythemia (ET) adversely affect both overall (SF3B1, SRSF2 in ET and SRSF2 in PV) and myelofibrosis-free (U2AF1, SF3B1 in ET) survival. This review discusses current knowledge of the molecular landscape of MPN, and how the availability of those molecular information may impact patient management.

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“…These mutations are mutually exclusive and do show correlation with disease phenotype and prognosis [5][6][7]. Additional mutations in genes involved in epigenetic regulation, affecting the RAS signaling pathway or the tumor suppressor TP53 also play a fundamental role in the transformation of the malignant cell and, therefore, in its clinical expression [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Clinical Characteristics and Outcomes of Patients with Primary and Secondary Myelofibrosis According to the Genomic Classification Using Targeted Next-Generation Sequencing

Garrote

López‐Guerra

Arellano‐Rodrigo

et al. 2023

Cancers

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Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape, clinical presentation, and outcomes. The aim of our work is to evaluate the genomic classification of MF considering whether it is primary or secondary. One-hundred seventy-five patients, 81 with primary MF (PMF) and 94 with secondary MF (SMF) were hierarchically allocated into eight molecular groups. We found that TP53 disruption/aneuploidy (n = 16, 9%) was more frequent (12% versus 6%) and showed higher allele burden (57% versus 15%, p = 0.01) in SMF than in PMF, and was associated with shorter survival (median 3.5 years). Mutations in chromatin/spliceosome genes (n = 72, 41%) represented the most frequent genomic group in PMF. Homozygous JAK2 mutation (n = 40, 23%) was enriched with old patients with SMF after long-standing polycythemia vera, whereas MF with heterozygous JAK2 mutation (n = 22, 13%) was similarly distributed among PMF and SMF. MF with CALR mutation (n = 19, 11%) predominated in post-essential thrombocythemia MF. The remaining genomic groups were infrequent. TP53 disruption, chromatin/spliceosome mutation, and homozygous JAK2 mutation were associated with significantly shorter survival and higher risk of progression. In conclusion, genomic classification reveals different pathogenic pathways between PMF and SMF and provides relevant information regarding disease phenotype and outcomes.

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Spliceosome mutations are common in persons with myeloproliferative neoplasm-associated myelofibrosis with RBC-transfusion-dependence and correlate with response to pomalidomide

Abstract: for the RESUME trialists (2020). Spliceosome mutations are common in persons with myeloproliferative neoplasm-associated myelofibrosis with RBC-transfusion-dependence and correlate with response to pomalidomide. Leukemia.

Cited by 8 publications

References 13 publications

Lenalidomide: A double‐edged sword for concomitant multiple myeloma and post‐essential thrombocythemia myelofibrosis

Lenalidomide: A double‐edged sword for concomitant multiple myeloma and post‐essential thrombocythemia myelofibrosis

<p>Impact of Mutational Profile on the Management of Myeloproliferative Neoplasms: A Short Review of the Emerging Data</p>

Clinical Characteristics and Outcomes of Patients with Primary and Secondary Myelofibrosis According to the Genomic Classification Using Targeted Next-Generation Sequencing

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