Loss of Dnmt3a increases self-renewal and resistance to pegIFN-α in JAK2-V617F-positive myeloproliferative neoplasms.

Autor:	Usart M; Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland., Stetka J; Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland.; Department of Biology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic., Luque Paz D; University of Angers, Nantes Université, Centre Hospitalier Universitaire Angers, INSERM, Centre National de la Recherche Scientifique, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, Angers, France., Hansen N; Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland., Kimmerlin Q; Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland., Almeida Fonseca T; Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland., Lock M; Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland., Kubovcakova L; Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland., Karjalainen R; Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland., Hao-Shen H; Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland., Börsch A; Department of Biomedicine, Bioinformatics, University of Basel and University Hospital Basel, Basel, Switzerland.; Swiss Institute of Bioinformatics, Basel, Switzerland., El Taher A; Department of Biomedicine, Bioinformatics, University of Basel and University Hospital Basel, Basel, Switzerland.; Swiss Institute of Bioinformatics, Basel, Switzerland., Schulz J; Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland., Leroux JC; Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland., Dirnhofer S; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland., Skoda RC; Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Jun 13; Vol. 143 (24), pp. 2490-2503.
DOI:	10.1182/blood.2023020270
Abstrakt:	Abstract: Pegylated interferon alfa (pegIFN-α) can induce molecular remissions in patients with JAK2-V617F-positive myeloproliferative neoplasms (MPNs) by targeting long-term hematopoietic stem cells (LT-HSCs). Additional somatic mutations in genes regulating LT-HSC self-renewal, such as DNMT3A, have been reported to have poorer responses to pegIFN-α. We investigated whether DNMT3A loss leads to alterations in JAK2-V617F LT-HSC functions conferring resistance to pegIFN-α treatment in a mouse model of MPN and in hematopoietic progenitors from patients with MPN. Long-term treatment with pegIFN-α normalized blood parameters and reduced splenomegaly and JAK2-V617F chimerism in single-mutant JAK2-V617F (VF) mice. However, pegIFN-α in VF;Dnmt3aΔ/Δ (VF;DmΔ/Δ) mice worsened splenomegaly and failed to reduce JAK2-V617F chimerism. Furthermore, LT-HSCs from VF;DmΔ/Δ mice compared with VF were less prone to accumulate DNA damage and exit dormancy upon pegIFN-α treatment. RNA sequencing showed that IFN-α induced stronger upregulation of inflammatory pathways in LT-HSCs from VF;DmΔ/Δ than from VF mice, indicating that the resistance of VF;DmΔ/Δ LT-HSC was not due to failure in IFN-α signaling. Transplantations of bone marrow from pegIFN-α-treated VF;DmΔ/Δ mice gave rise to more aggressive disease in secondary and tertiary recipients. Liquid cultures of hematopoietic progenitors from patients with MPN with JAK2-V617F and DNMT3A mutation showed increased percentages of JAK2-V617F-positive colonies upon IFN-α exposure, whereas in patients with JAK2-V617F alone, the percentages of JAK2-V617F-positive colonies decreased or remained unchanged. PegIFN-α combined with 5-azacytidine only partially overcame resistance in VF;DmΔ/Δ mice. However, this combination strongly decreased the JAK2-mutant allele burden in mice carrying VF mutation only, showing potential to inflict substantial damage preferentially to the JAK2-mutant clone. (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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