Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients.

Michelino Di Rosa,Ignazio Barbagallo,Giuseppe A Palumbo,Giuseppe Musumeci,Cesarina Giallongo,Giovanni Li Volti,Alessandra Romano,Paola Castrogiovanni,Daniele Tibullo,Rosa Imbesi

doi:10.3390/ijms21082926

Michelino Di Rosa, Ignazio Barbagallo + Show 8 more

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https://doi.org/10.3390/ijms21082926

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Abstract

Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by stem-cell-derived clonal over-proliferation of mature myeloid lineages, bone marrow fibrosis, osteosclerosis, defective erythropoiesis, and pro-inflammatory cytokine over-expression. The aim of the present study was to highlight possible differences in the transcriptome among CD34+ cells from peripheral blood (PB) of PMF patients. Therefore, we merged two microarray datasets of healthy control subjects and PMF (34 JAK2V617F MUTATED and 28 JAK2 wild-type). The GO analysis of upregulated genes revealed enrichment for JAK2/STAT1 pathway gene set in PB CD34+ cells of PMF patients with and without the JAK2V617F mutation comparing to the healthy control subjects, and in particular a significant upregulation of immunoproteasome (IP)-belonging genes as PSMB8, PSMB9, and PSMB10. A more detailed investigation of the IFN-gamma (IFNG) pathway also revealed that IFNG, IRF1, and IFNGR2 were significantly upregulated in PB CD34+ cells of PMF patients carrying the mutation for JAK2V617F compared to JAK2 wild-type PMF patients. Finally, we showed an upregulation of HLA-class I genes in PB CD34+ cells from PMF JAK2V617F mutated patients compared to JAK2 wild-type and healthy controls. In conclusion, our results demonstrate that IPs and IFNG pathways could be involved in PMF disease and in particular in patients carrying the JAK2V617F mutation.

Highlights

Primary Myelofibrosis (PMF) is a Philadelphia-negative myeloproliferative neoplasm (MPNs), characterized by stem cell-derived clonal proliferation of one or more myeloid lineage cells [1]
Lack of clinical efficacy of Bortez3oofm20ib in myelofibrosis may be linked to the need for blocking oncogenic driver mutations including Janus Kinsausrevi2vaaln[d38C].aLlraectkicouflicnli.nical efficacy of Bortezomib in myelofibrosis may be linked to the need for bloWckitihngthoencaoigmenoifc iddreivnetrifmyiuntgatnioenws ipncolsusdibinlge JmanoulescKuilnaarstea2rgaentds,Cwalereutisceudlinth. e datasets available in GEODaWtasiteht [t3h9e]aiinmorodfeirdetontdifeysicnrgibneetwhepmosasiinbldeimffeorleencucelasrintatrhgeettsr,awnsecruispetdomtheeodfaCtaDse3t4s+ahveaimlaabtloepionietic proGgEenOiDtoartacseeltls[3c9ir]cuinlatoinrdgerintopedriepshcreibrael tbhleoomd a(iPnB)dioffferheenacletshyinintdhievidtruanalssc,riapntodmien owf ilCdD-ty34p+e or JAKh2eVm6a1t7oFpmoiuettiactepdroPgMenFitporatcieelnlstsc,itrrcyuilnagtintgo dinrapweraipshtearratlinbgloloinde(fPoBr)fuoftuhreeailtnhvyesintidgiavtiidounasl.s, and in wild-type or JAK2V617F mutated PMF patients, trying to draw a starting line for future investigations
We have showed that there was a significant downregulation in IFNG (p < 0.001) expression levels in JAK2 wild-type PMF peripheral blood (PB) CD34+ cells compared to healthy controls subjects

Summary

Introduction

Primary Myelofibrosis (PMF) is a Philadelphia-negative myeloproliferative neoplasm (MPNs), characterized by stem cell-derived clonal proliferation of one or more myeloid lineage cells [1] It is associated with bone marrow fibrosis, osteosclerosis, angiogenesis, extramedullary hematopoiesis, and adnormal cytokine levels [2]. In cells of hematopoietic origins, the classical proteasome is replaced by a different proteasome with an immunological role called immunoproteasome (IPs) [27] The origin of this term arises from the fact that it was discovered during studies of antigen presentation on the cell surface for T-cell recognition to stimulate the immune response in collaboration with major histocompatibility class I (MHC class I) molecules. Lack of clinical efficacy of Bortez3oofm20ib in myelofibrosis may be linked to the need for blocking oncogenic driver mutations including Janus Kinsausrevi2vaaln[d38C].aLlraectkicouflicnli.nical efficacy of Bortezomib in myelofibrosis may be linked to the need for bloWckitihngthoencaoigmenoifc iddreivnetrifmyiuntgatnioenws ipncolsusdibinlge JmanoulescKuilnaarstea2rgaentds,Cwalereutisceudlinth. e datasets available in GEODaWtasiteht [t3h9e]aiinmorodfeirdetontdifeysicnrgibneetwhepmosasiinbldeimffeorleencucelasrintatrhgeettsr,awnsecruispetdomtheeodfaCtaDse3t4s+ahveaimlaabtloepionietic proGgEenOiDtoartacseeltls[3c9ir]cuinlatoinrdgerintopedriepshcreibrael tbhleoomd a(iPnB)dioffferheenacletshyinintdhievidtruanalssc,riapntodmien owf ilCdD-ty34p+e or JAKh2eVm6a1t7oFpmoiuettiactepdroPgMenFitporatcieelnlstsc,itrrcyuilnagtintgo dinrapweraipshtearratlinbgloloinde(fPoBr)fuoftuhreeailtnhvyesintidgiavtiidounasl.s, and in wild-type or JAK2V617F mutated PMF patients, trying to draw a starting line for future investigations

Results

Discussion

GSE41812 GPL13667

Data Processing and Experimental Design

Statistical Analysis

Conclusions