Phenformin increases early hematopoietic progenitors in the Jak2(V617F) murine model

Author(s):Show less -

Alves-Silva, Antonio Bruno ^{[1, 2]} ; Fenerich, Bruna Alves ^{[1, 2]} ; Fonseca, Natasha Peixoto ^{[1, 2]} ; Fernandes, Jaqueline Cristina ^{[1, 2]} ; Coelho-Silva, Juan Luiz ^{[1, 2]} ; Pereira-Martins, Diego Antonio ^{[3, 2, 4]} ; Bianco, Thiago Mantello ^{[1, 2]} ; Scheucher, Priscila Santos ^[1] ; Rego, Eduardo Magalhaes ^{[3, 2, 4]} ; Chahud, Fernando ^[5] ; Machado-Neto, Joao Agostinho ^[6] ; Figueiredo-Pontes, Lorena Lobo ^{[1, 2]} ; Traina, Fabiola ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Med Imaging Hematol & Oncol, Ribeirao Preto - Brazil

^[2] Sao Paulo Res Fdn, Ctr Cell Based Therapy, Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, Ribeirao Preto - Brazil

^[4] Univ Sao Paulo, Hematol Div, LIM31, Med Sch, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Dept Pathol & Legal Med, Ribeirao Preto Med Sch, Ribeirao Preto - Brazil

^[6] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil

• Document type: Journal article
• Source: INVESTIGATIONAL NEW DRUGS; JAN 2022.
• Web of Science Citations: 0

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 JAK2(V617F) 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 Phenformin is a biguanide that has been used to treat diabetes, but was withdrawn due to its potential to cause lactic acidosis in patients.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(V617F)-knockin MPN mice. Results. In vitro phenformin treatment reduced cell viability and increased apoptosis in SET2 JAK2(V67F) cells. Long-term treatment with 40 mg/kg phenformin in Jak2(V617F) 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(V617F) 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(V617F)-knockin mice. Additional studies are necessary to further understand the effects of phenformin on early hematopoietic progenitors. (AU)

• FAPESP's process: 14/50947-7 - INCT 2014: in Stem Cell and Cell Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC