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Proteomic identification of proliferation and progression markers in human polycythemia vera stem and progenitor cells


Tan, Ge; Wolski, Witold Eryk; Kummer, Sandra; Hofstetter, Mara Carina; Theocharides, Alexandre P A; Manz, Markus G; Aebersold, Ruedi; Meier-Abt, Fabienne (2022). Proteomic identification of proliferation and progression markers in human polycythemia vera stem and progenitor cells. Blood Advances, 6(11):3480-3493.

Abstract

Polycythemia vera (PV) is a stem cell disorder characterized by hyperproliferation of the myeloid lineages and the presence of an activating JAK2 mutation. To elucidate mechanisms controlling PV stem and progenitor cell biology, we applied a recently developed highly sensitive data-independent acquisition mass spectrometry workflow to purified hematopoietic stem and progenitor cell (HSPC) subpopulations of patients with chronic and progressed PV. We integrated proteomic data with genomic, transcriptomic, flow cytometry and in vitro colony formation data.

Comparative analyses revealed added information gained by proteomic compared with transcriptomic data in 30% of proteins with changed expression in PV patients. Upregulated biological pathways in hematopoietic stem and multipotent progenitor cells (HSC/MPPs) of PV included MTOR, STAT and interferon signalling. We further identified a prominent reduction of clusterin (CLU) protein expression and a corresponding activation of NFĸB signalling in HSC/MPPs of untreated PV patients compared with controls.

Reversing the reduction of CLU and inhibiting NFĸB signalling decreased proliferation and differentiation of PV HSC/MPPs in vitro. Upon progression of PV, we identified upregulation of LGALS9 and SOCS2 protein expression in HSC/MPPs. Treatment of patients with hydroxyurea normalized the expression of CLU and NFĸB2, but not of LGALS9 and SOCS2. These findings expand the current understanding of the molecular pathophysiology underlying PV and provide new potential targets (CLU and NFĸB) for antiproliferative therapy in PV patients.

Abstract

Polycythemia vera (PV) is a stem cell disorder characterized by hyperproliferation of the myeloid lineages and the presence of an activating JAK2 mutation. To elucidate mechanisms controlling PV stem and progenitor cell biology, we applied a recently developed highly sensitive data-independent acquisition mass spectrometry workflow to purified hematopoietic stem and progenitor cell (HSPC) subpopulations of patients with chronic and progressed PV. We integrated proteomic data with genomic, transcriptomic, flow cytometry and in vitro colony formation data.

Comparative analyses revealed added information gained by proteomic compared with transcriptomic data in 30% of proteins with changed expression in PV patients. Upregulated biological pathways in hematopoietic stem and multipotent progenitor cells (HSC/MPPs) of PV included MTOR, STAT and interferon signalling. We further identified a prominent reduction of clusterin (CLU) protein expression and a corresponding activation of NFĸB signalling in HSC/MPPs of untreated PV patients compared with controls.

Reversing the reduction of CLU and inhibiting NFĸB signalling decreased proliferation and differentiation of PV HSC/MPPs in vitro. Upon progression of PV, we identified upregulation of LGALS9 and SOCS2 protein expression in HSC/MPPs. Treatment of patients with hydroxyurea normalized the expression of CLU and NFĸB2, but not of LGALS9 and SOCS2. These findings expand the current understanding of the molecular pathophysiology underlying PV and provide new potential targets (CLU and NFĸB) for antiproliferative therapy in PV patients.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology and Hematology
04 Faculty of Medicine > Institute of Medical Genetics
04 Faculty of Medicine > Functional Genomics Center Zurich
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Myeloid Neoplasia,
Language:English
Date:14 June 2022
Deposited On:17 Jan 2022 05:29
Last Modified:26 Apr 2024 01:39
Publisher:American Society of Hematology
ISSN:2473-9529
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1182/bloodadvances.2021005344
PubMed ID:35008095
  • Content: Published Version
  • Language: English
  • Content: Supplemental Material
  • Language: English
  • Description: Supplementary Methods