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ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE225396 | GEO | 2025/02/02

REPOSITORIES: GEO

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ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression II.

Project description:Myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), are clonal disorders driven by mutations in hematopoietic stem cells (HSCs). JAK2V617F is the most recurrent driver mutation in MPN and results in the constitutive activation of the JAK-STAT pathway. ZRSR2-loss is reported to cause mis-splicing of U12-type introns in myelodysplastic syndromes (MDS). Loss of function mutations in ZRSR2 have been found in a JAK2V617F-driven MPNs and are associated with disease progression and poor prognosis. However, the functional contribution of ZRSR2-loss to the pathogenesis and disease progression of MPN remains unknown. Using CRISPR-Cas9, we generated concomitant ZRSR2-loss in a JAK2V617F-driven human cell line and mouse model of MPN. RNA-Seq data demonstrates that ZRSR2-loss causes aberrant splicing in both human and murine cells, with the affect being more subtle in the murine context. Gene expression analysis in murine HSCs indicates that Zrsr2-loss biases lineage differentiation priming to megakaryocytes. However, Zrsr2-loss did not alter the severity or phenotype of the MPN in Jak2V617F mice. These results indicate that Zrsr2 mutations have limited impact on disease progression of Jak2V617F -driven MPN in vivo. Consistent with this, we find that ZRSR2 mutations are more frequently identified in genetically complex MPN patients carrying other high molecular risk mutations. In total, our findings demonstrate that ZRSR2-loss causes subtle mis-splicing in JAK2V617F-driven MPN that is not sufficient to drive disease progression in the absence of other high-risk mutations.

2025-02-02 | GSE225395 | GEO

ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression I.

2025-02-02 | GSE225394 | GEO

ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression

Project description:ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression

| PRJNA935389 | ENA

ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression II.

Project description:ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression II.

| PRJNA935393 | ENA

ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression I.

Project description:ZRSR2-loss causes aberrant splicing in a JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression I.

| PRJNA935391 | ENA

The ERK2-DBP domain opposes pathogenesis of a mouse JAK2V617F-driven myeloproliferative neoplasm.

Project description:Although Ras/mitogen-activated protein kinase (MAPK) signaling is activated in most human cancers, attempts to target this pathway using kinase-active site inhibitors have not typically led to durable clinical benefit. To address this shortcoming, we sought to test the feasibility of an alternative targeting strategy, focused on the ERK2 substrate binding domains, D and DEF binding pocket (DBP). Disabling the ERK2-DBP domain in mice caused baseline erythrocytosis. Consequently, we investigated the role of the ERK2-D and -DBP domains in disease, using a JAK2-dependent model of polycythemia vera (PV). Of note, inactivation of the ERK2-DBP domain promoted the progression of disease from PV to myelofibrosis, suggesting that the ERK2-DBP domain normally opposes progression. ERK2-DBP inactivation also prevented oncogenic JAK2 kinase (JAK2V617F) from promoting oncogene-induced senescence in vitro. The ERK2-DBP mutation attenuated JAK2-mediated oncogene-induced senescence by preventing the physical interaction of ERK2 with the transcription factor Egr1. Because inactivation of the ERK2-DBP created a functional ERK2 kinase limited to binding substrates through its D domain, these data suggested that the D domain substrates were responsible for promoting oncogene-induced progenitor growth and tumor progression and that pharmacologic targeting of the ERK2-D domain may attenuate cancer cell growth. Indeed, pharmacologic agents targeting the ERK2-D domain were effective in attenuating the growth of JAK2-dependent myeloproliferative neoplasm cell lines. Taken together, these data indicate that the ERK-D and -DBP domains can play distinct roles in the progression of neoplasms and that the D domain has the potential to be a potent therapeutic target in Ras/MAPK-dependent cancers.

| S-EPMC9335498 | biostudies-literature

SRSF2 mutation reduces polycythemia and impairs hematopoietic progenitor functions in JAK2V617F-driven myeloproliferative neoplasm.

Project description:SRSF2 mutations are found in association with JAK2V617F in myeloproliferative neoplasms (MPN), most frequently in myelofibrosis (MF). However, the contribution of SRSF2 mutation in JAK2V617F-driven MPN remains elusive. To investigate the consequences of SRSF2P95H and JAK2V617F mutations in MPN, we generated Cre-inducible Srsf2P95H/+Jak2V617F/+ knock-in mice. We show that co-expression of Srsf2P95H mutant reduced red blood cell, neutrophil, and platelet counts, attenuated splenomegaly but did not induce bone marrow fibrosis in Jak2V617F/+ mice. Furthermore, co-expression of Srsf2P95H diminished the competitiveness of Jak2V617F mutant hematopoietic stem/progenitor cells. We found that Srsf2P95H mutant reduced the TGF-β levels but increased the expression of S100A8 and S100A9 in Jak2V617F/+ mice. Furthermore, enforced expression of S100A9 in Jak2V617F/+ mice bone marrow significantly reduced the red blood cell, hemoglobin, and hematocrit levels. Overall, these data suggest that concurrent expression of Srsf2P95H and Jak2V617F mutants reduces erythropoiesis but does not promote the development of bone marrow fibrosis in mice.

| S-EPMC10682023 | biostudies-literature

JAK2V617F mRNA metabolism in myeloproliferative neoplasm cell lines.

Project description: Not available

| S-EPMC4080214 | biostudies-literature

Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm.

Project description:Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.

| S-EPMC7190923 | biostudies-literature

Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells.

Project description:We report a Jak2V617F knockin mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a significant selective competitive advantage over wild-type HSCs. In contrast, myeloid progenitor populations are expanded and skewed toward the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to JAK2V617F-positive MPN.

| S-EPMC2909585 | biostudies-literature

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