Mutations in <i><scp>SETBP</scp>1</i> are recurrent in myelodysplastic syndromes and often coexist with cytogenetic markers associated with disease progression

Fernández-Mercado, Marta; Pellagatti, Andrea; Genua, Cristina Di; Larráyoz, María José; Winkelmann, Nils; Aranaz, Paula; Burns, Adam; Schuh, Anna; Calasanz, Marı́a José; Cross, Nicholas C. P.; Boultwood, Jacqueline

doi:10.1111/bjh.12491

Cited by 37 publications

(34 citation statements)

References 15 publications

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“…It carries a poor prognosis 108,109 and shares some clinical and molecular features with CMML. Congenital JMML predisposition syndromes exist, particularly neurofibromatosis and Noonan syndrome, which converge on RAS signaling abnormalities and markedly increase the risk of developing JMML 110,111 JMML is a heterogeneous clinical entity in that some patients, particularly those with Noonan syn-…”

Section: Juvenile Myelomonocytic Leukemiamentioning

confidence: 99%

An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o n MDS/MPN: cytogenetic, molecular genetics and signaling abnormalitiesChromosome analysis using conventional cytogenetics and high-resolution single nucleotide polymorphism array karyotyping (SNP-A) reveals chromosome abnormalities in 70% of MDS/MPN patients. 7 Most of these are aneuploidies (trisomy 8, monosomy 7) or deletions (del7q, del13q, del20q); a minority have reciprocal translocations involving diverse tyrosine kinase (TK) fusion genes. 8,9 Some of these fusions are listed separately within the current WHO classification: 'myeloid and lymphoid neoplasms with eosinophilia' (MLN-eo) and abnormalities of PDGFRA, PDGFRB and FGFR1. Fusions involving other kinases are also seen in patients with MDS/MPN or MPNs. 10 Fusions involving PDGFRA, PDGFRB and ABL1 are important to recognize as they confer sensitivity to TK inhibitors (TKIs), such as imatinib. 11 Other fusions involving FGFR1 or JAK2 are insensitive to imatinib but may respond to ponatinib or ruxolitinib, respectively. [12][13][14][15][16] Most mutant genes fall into four functional classes: signaling, epigenetic, splicing and transcription ( Figure 2). [17][18][19][20] Signaling mutations result in aberrant activation of proliferative and anti-apoptotic pathways normally induced by growth factors (GFs). In addition to the TK gene fusions mentioned above, mutations have been described in GF receptors (CSF3R), downstream cytokine receptor signaling intermediates (JAK2, NRAS, KRAS) and negative regulators of signaling pathways (PTPN11, CBL, NF1). [21][22][23][24][25][26][27] Mutations involving RAS are demonstrable in 90% of JMML cases and may emerge as a defining feature of this condition. 28 Signaling mutations occur in approximately 50% of CMML patients and correlate with a myeloproliferative phenotype and enhancement of in vitro sensitivity to GM-CSF. 29 Up to 80% of patients with RARS-T have activated JAK-STAT signaling as a consequence of the presence of JAK2 V617F or mutations in MPL [encoding for the thrombopoietin receptor (Tpo-R)]. 30 In mice, abrogation of Notch signaling leads to a MDS/MPN phenotype, but its relevance in humans is unknown. 31 MDS/MPN: nuclear events -epigenetics, spliceosomes and transcription factorsMutations in genes encoding epigenetic regulators are common in MDS/MPN. [32][33][34][35] The most frequently mutated genes are TET2 and ASXL1, followed by SRSF2, IDH1/2, EZH2, SUZ12, EED and UTX. 36 The interaction between epigenetic mutations is complex, and apart from the general mutual exclusivity of TET2 and IDH1/2 mutations, no clear patterns have emerged. 37,38 Mutations in elements involved in the recognition and processing of 3'-mRNA splice sites are also common in MDS/MPN. 39 Around 50% of CMML patients have mutations involving SRSF2, with a further 20% exhibiting mutations in other splicing complex genes (SF3B1, U2AF35, U2AF65 and SF3A1). 34,35,40,41 In addition, SF3B1 mutations are present in 72% of patients with RARS-T. 42,43 These SF3B1 mutations are...

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Section: Juvenile Myelomonocytic Leukemiamentioning

confidence: 99%

An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms

et al. 2015

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“…To explore other possible mechanisms involved with the development of leukocytosis, we investigated eight cases for mutations of CSF3R, SETBP1, and SRSF2 genes. Truncation mutations of the receptor cytoplasmic domain for CSF3R have been recently identified as a highly sensitive and specific molecular marker for CNL [23][24][25] and SETBP1 is frequently mutated in atypical chronic myeloid leukemia 26 in other myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms 27 or chronic myelomonocytic leukemia. 28 SRSF2 mutations has been described in 47% of chronic myelomonocytic leukemia 29 and, although less frequently, in other types of myelodysplastic and myeloproliferative neoplasms.…”

Section: Modern Pathology (2015) 28 1448-1457mentioning

confidence: 99%

Neutrophilic leukocytosis in advanced stage polycythemia vera: hematopathologic features and prognostic implications

et al. 2015

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“…Importantly, however, several studies have shown SETBP1 to be a poor prognostic marker in myeloid diseases. 66,67,71 Alterations in microRNA (miR) expression are involved in the initiation, progression, and metastasis of human tumors, and germline mutations in specific miR clusters are thought to be associated with inherited cancer predispotions. 72 The let-7 miR family is known to target Ras, and a SNP in a let-7 binding site in the KRAS 39 untranslated region yielded KRAS overexpression and an increased risk for nonsmall cell lung cancer.…”

Section: 55mentioning

confidence: 99%

Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia

Chang

Dvorak

Loh

2014

Blood

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Juvenile myelomonocytic leukemia (JMML) is a typically aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukemia, a similar disease in adults. Although the current standard of care for patients with JMML relies on allogeneic hematopoietic stem cell transplant, relapse is the most frequent cause of treatment failure. Tremendous progress has been made in defining the genomic landscape of JMML. Insights from cancer predisposition syndromes have led to the discovery of nearly 90% of driver mutations in JMML, all of which thus far converge on the Ras signaling pathway. This has improved our ability to accurately diagnose patients, develop molecular markers to measure disease burden, and choose therapeutic agents to test in clinical trials. This review emphasizes recent advances in the field, including mapping of the genomic and epigenome landscape, insights from new and existing disease models, targeted therapeutics, and future directions.

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Mutations in SETBP1 are recurrent in myelodysplastic syndromes and often coexist with cytogenetic markers associated with disease progression

Cited by 37 publications

References 15 publications

An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms

An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms

Neutrophilic leukocytosis in advanced stage polycythemia vera: hematopathologic features and prognostic implications

Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia

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