Dataset Information

Metformin exerts multitarget antileukemia activity in JAK2^V617F-positive myeloproliferative neoplasms.

ABSTRACT: The recurrent gain-of-function JAK2^V617F mutation confers growth factor-independent proliferation for hematopoietic cells and is a major contributor to the pathogenesis of myeloproliferative neoplasms (MPN). The lack of complete response in most patients treated with the JAK1/2 inhibitor ruxolitinib indicates the need for identifying novel therapeutic strategies. Metformin is a biguanide that exerts selective antineoplastic activity in hematological malignancies. In the present study, we investigate and compare effects of metformin and ruxolitinib alone and in combination on cell signaling and cellular functions in JAK2^V617F-positive cells. In JAK2^V617F-expressing cell lines, metformin treatment significantly reduced cell viability, cell proliferation, clonogenicity, and cellular oxygen consumption and delayed cell cycle progression. Metformin reduced cyclin D1 expression and RB, STAT3, STAT5, ERK1/2 and p70S6K phosphorylation. Metformin plus ruxolitinib demonstrated more intense reduction of cell viability and induction of apoptosis compared to monotherapy. Notably, metformin reduced Ba/F3 JAK2^V617F tumor burden and splenomegaly in Jak2^V617F knock-in-induced MPN mice and spontaneous erythroid colony formation in primary cells from polycythemia vera patients. In conclusion, metformin exerts multitarget antileukemia activity in MPN: downregulation of JAK2/STAT signaling and mitochondrial activity. Our exploratory study establishes novel molecular mechanisms of metformin and ruxolitinib action and provides insights for development of alternative/complementary therapeutic strategies for MPN.

SUBMITTER: Machado-Neto JA

PROVIDER: S-EPMC5833553 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Metformin exerts multitarget antileukemia activity in JAK2<sup>V617F</sup>-positive myeloproliferative neoplasms.

Machado-Neto João Agostinho JA Fenerich Bruna Alves BA Scopim-Ribeiro Renata R Eide Christopher A CA Coelho-Silva Juan Luiz JL Dechandt Carlos Roberto Porto CRP Fernandes Jaqueline Cristina JC Rodrigues Alves Ana Paula Nunes APN Scheucher Priscila Santos PS Simões Belinda Pinto BP Alberici Luciane Carla LC de Figueiredo Pontes Lorena Lôbo LL Tognon Cristina E CE Druker Brian J BJ Rego Eduardo Magalhães EM Traina Fabiola F

Cell death & disease 20180222 3

The recurrent gain-of-function JAK2<sup>V617F</sup> mutation confers growth factor-independent proliferation for hematopoietic cells and is a major contributor to the pathogenesis of myeloproliferative neoplasms (MPN). The lack of complete response in most patients treated with the JAK1/2 inhibitor ruxolitinib indicates the need for identifying novel therapeutic strategies. Metformin is a biguanide that exerts selective antineoplastic activity in hematological malignancies. In the present study, ...[more]

PMID: 29472557

Similar Datasets

Project description:The classic BCR-ABL1-negative myeloproliferative neoplasm (MPN) is a highly heterogeneous hematologic tumor that includes three subtypes, namely polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). Despite having the same JAK2V617F mutation, the clinical manifestations of these three subtypes of MPN differ significantly, which suggests that the bone marrow (BM) immune microenvironment may also play an important role. In recent years, several studies have shown that peripheral blood monocytes play an important role in promoting MPN. However, to date, the role of BM monocytes/macrophages in MPN and their transcriptomic alterations remain incompletely understood. The purpose of this study was to clarify the role of BM monocytes/macrophages in MPN patients with the JAK2V617F mutation. MPN patients with the JAK2V617F mutation were enrolled in this study. We investigated the roles of monocytes/macrophages in the BM of MPN patients, using flow cytometry, monocyte/macrophage enrichment sorting, cytospins and Giemsa-Wright staining, and RNA-seq. Pearson correlation coefficient analysis was also used to detect the correlation between BM monocytes/macrophages and the MPN phenotype. In the present study, the proportion of CD163+ monocytes/macrophages increased significantly in all three subtypes of MPN. Interestingly, the percentages of CD163+ monocytes/macrophages are positively correlated with HGB in PV patients and PLT in ET patients. In contrast, the percentages of CD163+ monocytes/macrophages are negatively correlated with HGB and PLT in PMF patients. It was also found that CD14+CD16+ monocytes/macrophages increased and correlated with MPN clinical phenotypes. RNA-seq analyses demonstrated that the transcriptional expressions of monocytes/macrophages in MPN patients are relatively distinct. Gene expression profiles of BM monocytes/macrophages suggest a specialized function in support of megakaryopoiesis in ET patients. In contrast, BM monocytes/macrophages yielded a heterogeneous status in the support or inhibition of erythropoiesis. Significantly, BM monocytes/macrophages shaped an inflammatory microenvironment, which, in turn, promotes myelofibrosis. Thus, we characterized the roles of increased monocytes/macrophages in the occurrence and progression of MPNs. Our findings of the comprehensive transcriptomic characterization of BM monocytes/macrophages provide important resources to serve as a basis for future studies and future targets for the treatment of MPN patients.

Dataset Information

Metformin exerts multitarget antileukemia activity in JAK2^V617F-positive myeloproliferative neoplasms.

Publications

Metformin exerts multitarget antileukemia activity in JAK2<sup>V617F</sup>-positive myeloproliferative neoplasms.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Metformin exerts multitarget antileukemia activity in JAK2V617F-positive myeloproliferative neoplasms.

Publications

Metformin exerts multitarget antileukemia activity in JAK2<sup>V617F</sup>-positive myeloproliferative neoplasms.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Metformin exerts multitarget antileukemia activity in JAK2^V617F-positive myeloproliferative neoplasms.