2. Academic Validation
  3. Phenformin increases early hematopoietic progenitors in the Jak2V617F murine model

Phenformin increases early hematopoietic progenitors in the Jak2V617F murine model

  • Invest New Drugs. 2022 Jun;40(3):576-585. doi: 10.1007/s10637-022-01212-y.
Antônio Bruno Alves-Silva 1 2,  Bruna Alves Fenerich 1 2,  Natasha Peixoto Fonseca 1 2,  Jaqueline Cristina Fernandes 1 2,  Juan Luiz Coelho-Silva 1 2,  Diego Antonio Pereira-Martins 2 3 4,  Thiago Mantello Bianco 1 2,  Priscila Santos Scheucher 1,  Eduardo Magalhães Rego 2 3 4,  Fernando Chahud 5,  João Agostinho Machado-Neto 6,  Lorena Lôbo Figueiredo-Pontes 1 2,  Fabiola Traina 7 8
Affiliations

Affiliations

  • 1 Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.
  • 2 Center for Cell Based Therapy, São Paulo Research Foundation, Ribeirão Preto, Brazil.
  • 3 Department of Internal Medicine, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.
  • 4 Hematology Division, Medical School of University of São Paulo, LIM31, São Paulo, Brazil.
  • 5 Departament of Pathology and Legal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, Brazil.
  • 6 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
  • 7 Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil. [email protected].
  • 8 Center for Cell Based Therapy, São Paulo Research Foundation, Ribeirão Preto, Brazil. [email protected].
PMID: 35015172 DOI: 10.1007/s10637-022-01212-y
Abstract

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 JAK2V617F 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 Phenformin is a biguanide that has been used to treat diabetes, but was withdrawn due to its potential to cause lactic acidosis in patients.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 JAK2V617F-knockin MPN mice.

Results: In vitro phenformin treatment reduced cell viability and increased Apoptosis in SET2 JAK2V67F cells. Long-term treatment with 40 mg/kg phenformin in JAK2V617F 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 JAK2V617F 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 JAK2V617F-knockin mice. Additional studies are necessary to further understand the effects of phenformin on early hematopoietic progenitors.

Keywords

Biguanide; JAK2; Murine model; Myeloproliferative neoplasms; Phenformin; Polycythemia vera.

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