Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms

Jayavelu, Ashok Kumar; Schnöder, Tina M.; Perner, Florian; Herzog, Carolin; Meiler, Arno; Krishnamoorthy, Gurumoorthy; Huber, Nicolas; Mohr, Juliane; Edelmann-Stephan, Bärbel; Austin, Rebecca; Brandt, Sabine; Palandri, Francesca; Schröder, Nicolas W.J.; Isermann, Berend; Edlich, Frank; Sinha, Amit; Ungelenk, Martin; Hübner, Christian A.; Zeiser, Robert; Rahmig, Susann; Waskow, Claudia; Coldham, Iain; Ernst, Thomas; Hochhaus, Andreas; Jilg, Stefanie; Jost, Philipp J.; Mullally, Ann; Bullinger, Lars; Mertens, Peter R.; Lane, Steven; Mann, Matthias; Heidel, Florian H.

doi:10.1038/s41586-020-2968-3

Cited by 112 publications

(111 citation statements)

References 37 publications

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“…Due to missing value propagation for low input samples across TMT cassettes, we recommend using the microscaled phosphoproteome approach only for up to four plexes, with up to 64 samples in TMT16-mode, until better methods with improved reporter ion sensitivity are developed. Previous cancer studies with 45 medulloblastoma cases 55 , 27 breast cancer tumors 56 or 38 prostate cancer samples 57 and drug response profiling studies with 48 Jak2-mutated neoplasms 58 show that these cohort sizes can already be useful to molecularly characterize cancer subtypes and help in the discovery of future biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive micro-scaled proteome and phosphoproteome characterization of archived retrospective cancer repositories

et al. 2021

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Formalin-fixed paraffin-embedded (FFPE) tissues are a valuable resource for retrospective clinical studies. Here, we evaluate the feasibility of (phospho-)proteomics on FFPE lung tissue regarding protein extraction, quantification, pre-analytics, and sample size. After comparing protein extraction protocols, we use the best-performing protocol for the acquisition of deep (phospho-)proteomes from lung squamous cell and adenocarcinoma with >8,000 quantified proteins and >14,000 phosphosites with a tandem mass tag (TMT) approach. With a microscaled approach, we quantify 7,000 phosphosites, enabling the analysis of FFPE biopsies with limited tissue amounts. We also investigate the influence of pre-analytical variables including fixation time and heat-assisted de-crosslinking on protein extraction efficiency and proteome coverage. Our improved workflows provide quantitative information on protein abundance and phosphosite regulation for the most relevant oncogenes, tumor suppressors, and signaling pathways in lung cancer. Finally, we present general guidelines to which methods are best suited for different applications, highlighting TMT methods for comprehensive (phospho-)proteome profiling for focused clinical studies and label-free methods for large cohorts.

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Section: Discussionmentioning

confidence: 99%

Comprehensive micro-scaled proteome and phosphoproteome characterization of archived retrospective cancer repositories

et al. 2021

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“…This therapeutic efficacy is deemed to be based on a resensitization to JAK2 inhibition through different mechanisms, including restoration of homodimeric JAK‐STAT signaling 31 . However, other pathways may contribute to resistance to ruxolitinib and may be overcome with drug discontinuation 32 . The finding that only the use of high ruxolitinib doses (>10 mg twice daily) was associated with an increased probability of spleen and symptom improvements corroborates the positive relationship between dose and response shown in the COMFORT studies and by real‐world evidence 2,33,34 …”

Section: Discussionmentioning

confidence: 99%

Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome

Palandri

Tiribelli

Breccia³

et al. 2021

Cancer

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BACKGROUND After ruxolitinib discontinuation, the outcome of patients with myelofibrosis (MF) is poor with scarce therapeutic possibilities. METHODS The authors performed a subanalysis of an observational, retrospective study (RUX‐MF) that included 703 MF patients treated with ruxolitinib to investigate 1) the frequency and reasons for ruxolitinib rechallenge, 2) its therapeutic effects, and 3) its impact on overall survival. RESULTS A total of 219 patients (31.2%) discontinued ruxolitinib for ≥14 days and survived for ≥30 days. In 60 patients (27.4%), ruxolitinib was rechallenged for ≥14 days (RUX‐again patients), whereas 159 patients (72.6%) discontinued it permanently (RUX‐stop patients). The baseline characteristics of the 2 cohorts were comparable, but discontinuation due to a lack/loss of spleen response was lower in RUX‐again patients (P = .004). In comparison with the disease status at the first ruxolitinib stop, at its restart, there was a significant increase in patients with large splenomegaly (P < .001) and a high Total Symptom Score (TSS; P < .001). During the rechallenge, 44.6% and 48.3% of the patients had spleen and symptom improvements, respectively, with a significant increase in the number of patients with a TSS reduction (P = .01). Although the use of a ruxolitinib dose > 10 mg twice daily predicted better spleen (P = .05) and symptom improvements (P = .02), the reasons for/duration of ruxolitinib discontinuation and the use of other therapies before rechallenge were not associated with rechallenge efficacy. At 1 and 2 years, 33.3% and 48.3% of RUX‐again patients, respectively, had permanently discontinued ruxolitinib. The median overall survival was 27.9 months, and it was significantly longer for RUX‐again patients (P = .004). CONCLUSIONS Ruxolitinib rechallenge was mainly used in intolerant patients; there were clinical improvements and a possible survival advantage in many cases, but there was a substantial rate of permanent discontinuation. Ruxolitinib rechallenge should be balanced against newer therapeutic possibilities.

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“…STAT5 transcriptional activity is upregulated by the expression of JAK2 V617F in cell lines [ 37 ]. In analysis of ex vivo colony forming assays from ET and PV patients, transcriptional analysis demonstrated an enrichment of STAT5A targets with nuclear phosphorylation of STAT5A identified in JAK2 V617F position colonies from both ET and PV patients but not wild type colonies whilst a recent phospho-proteomics approach identified STAT5 and STAT3 as differentially phosphorylated in JAK2 V617F mouse haematopoietic cells [ 58 , 59 ]. Conditional expression of a null STAT5a/b gene resulted in a failure of a JAK2 V617F mouse model to develop polycythaemia but did not abrogate the risk of myelofibrosis [ 60 ].…”

Section: Jak/stat Signalling In Mpnmentioning

confidence: 99%

“…This results in an alteration in JAK2-ERK signalling to maintain the JAK2 V617F clones. JAK2 mutant cells are sensitised to the JAK inhibitor ruxolitinib after inactivation of YBX1, a splicing enzyme [ 59 ].…”

Section: Epigenetic Dysregulationmentioning

confidence: 99%

Molecular pathogenesis of the myeloproliferative neoplasms

2021

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The Philadelphia negative myeloproliferative neoplasms (MPN) compromise a heterogeneous group of clonal myeloid stem cell disorders comprising polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Despite distinct clinical entities, these disorders are linked by morphological similarities and propensity to thrombotic complications and leukaemic transformation. Current therapeutic options are limited in disease-modifying activity with a focus on the prevention of thrombus formation. Constitutive activation of the JAK/STAT signalling pathway is a hallmark of pathogenesis across the disease spectrum with driving mutations in JAK2, CALR and MPL identified in the majority of patients. Co-occurring somatic mutations in genes associated with epigenetic regulation, transcriptional control and splicing of RNA are variably but recurrently identified across the MPN disease spectrum, whilst epigenetic contributors to disease are increasingly recognised. The prognostic implications of one MPN diagnosis may significantly limit life expectancy, whilst another may have limited impact depending on the disease phenotype, genotype and other external factors. The genetic and clinical similarities and differences in these disorders have provided a unique opportunity to understand the relative contributions to MPN, myeloid and cancer biology generally from specific genetic and epigenetic changes. This review provides a comprehensive overview of the molecular pathophysiology of MPN exploring the role of driver mutations, co-occurring mutations, dysregulation of intrinsic cell signalling, epigenetic regulation and genetic predisposing factors highlighting important areas for future consideration.

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Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms

Abstract: This is a repository copy of Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms.

Cited by 112 publications

References 37 publications

Comprehensive micro-scaled proteome and phosphoproteome characterization of archived retrospective cancer repositories

Comprehensive micro-scaled proteome and phosphoproteome characterization of archived retrospective cancer repositories

Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome

Molecular pathogenesis of the myeloproliferative neoplasms

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