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Phenformin increases early hematopoietic progenitors in the Jak2V617F murine model.
- Source :
- Investigational New Drugs; Jun2022, Vol. 40 Issue 3, p576-585, 10p
- Publication Year :
- 2022
-
Abstract
- Summary: Background. Myeloproliferative neoplasms (MPN) are disorders characterized by an alteration at the hematopoietic stem cell (HSC) level, where the JAK2 mutation is the most common genetic alteration found in classic MPN (polycythemia vera, essential thrombocythemia, and primary myelofibrosis). We and others previously demonstrated that metformin reduced splenomegaly and platelets counts in peripheral blood in JAK2<superscript>V617F</superscript> pre-clinical MPN models, which highlighted the antineoplastic potential of biguanides for MPN treatment. Phenformin is a biguanide that has been used to treat diabetes, but was withdrawn due to its potential to cause lactic acidosis in patients. Aims. We herein aimed to investigate the effects of phenformin in MPN disease burden and stem cell function in Jak2<superscript>V617F</superscript>-knockin MPN mice. Results. In vitro phenformin treatment reduced cell viability and increased apoptosis in SET2 JAK2<superscript>V67F</superscript> cells. Long-term treatment with 40 mg/kg phenformin in Jak2<superscript>V617F</superscript> knockin mice increased the frequency of LSK, myeloid progenitors (MP), and multipotent progenitors (MPP) in the bone marrow. Phenformin treatment did not affect peripheral blood counts, spleen weight, megakaryocyte count, erythroid precursors frequency, or ex vivo clonogenic capacity. Ex vivo treatment of bone marrow cells from Jak2<superscript>V617F</superscript> knockin mice with phenformin did not affect hematologic parameters or engraftment in recipient mice. Conclusions. Phenformin increased the percentages of LSK, MP, and MPP populations, but did not reduce disease burden in Jak2<superscript>V617F</superscript>-knockin mice. Additional studies are necessary to further understand the effects of phenformin on early hematopoietic progenitors. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01676997
- Volume :
- 40
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Investigational New Drugs
- Publication Type :
- Academic Journal
- Accession number :
- 156839854
- Full Text :
- https://doi.org/10.1007/s10637-022-01212-y