Dados do Trabalho

Título

Formin-like protein 1 (FMNL1) expression in myeloid neoplasms: perspectives on biological functions and response to antineoplastic agents

Introdução

Myeloid neoplasms result from molecular alterations in hematopoietic stem cells. Acute myeloid leukemia (AML) is one of the myeloid neoplasms with the worst clinical outcomes. Advances in understanding the molecular complexity of myeloid neoplasms have translated into new prognostic markers and targeted therapies. The FMNL1 gene participates in the proliferation and migration of leukemia cells, but its expression and participation in normal and neoplastic hematopoiesis are still not understood.

Objetivo

The present study aimed to characterize the expression of FMNL1 in normal and malignant myelopoiesis, as well as its impact on survival outcomes, clinical characteristics, and biological functions in patients with AML.

Métodos

FMNL1 expression data in different populations of hematopoietic cells were obtained from GSE24759 study. NB4 cells were induced to differentiate with ATRA and FMNL1 expression was evaluated by qPCR and Western Blot. Gene and protein levels of FMNL1 were also characterized in a panel with 12 leukemia cell lines. FMNL1 transcript levels in samples obtained from healthy donors and patients with myeloid neoplasia (SMD, LMMC, LMC, and AML) were derived from the AmaZonia! 2008. Gene expression, genetic and clinical data from the AML TCGA study were obtained from cBioPortal. Data related to ex vivo assays in AML patients and cell lines were obtained from the Beat AML and Lee et al studies (Nat. Commun. 2018). Correlation, association, and comparison analyses between groups were performed using Spearman, Fisher, and Mann-Whitney tests. Functional genomic analysis was performed by GSEA and Gene Ontology (GO). Log-rank tests and Cox regression were used for survival estimates. FDR<0.25 and p value<0.05 were considered significant.

Resultados

FMNL1 expression is higher in granulocytic and monocytic subpopulations and lower in erythroid and megakaryocytic subpopulations. In NB4 cells, induction of cell differentiation increases FMNL1 expression (p < 0.05). FMNL1 was widely expressed in myeloid leukemia cell lines. High expression of FMNL1 was observed in patients with CML and AML (p < 0.05). In AML patients, FMNL1 levels did not impact survival outcomes (p > 0.05). The highest levels of FMNL1 were observed in AML patients with complex karyotypes. In functional genomic analyses, FMNL1 expression was associated with several biological and molecular processes, including MYC targets, E2F targets, G2/M checkpoint, p53 pathway, interferon alpha response, interferon-gamma response, TNF signaling via NFκB, TGFβ signaling, IL6/JAK/STAT3 signaling, IL2/STAT5 signaling, KRAS signaling, and NOTCH signaling. GO analyses indicate an activation of myeloid cell-mediated immune responses, including granulocytes, and cell adhesion. In ex vivo assays with primary cells from AML patients and AML cell lines, FMNL1 was associated with sensitivity and resistance to several drugs, including cytarabine.

Conclusões

FMNL1 may have an important role in the differentiation and function of granulocytes. FMNL1 expression is elevated in patients with CML and AML. The differential expression of FMNL1 is associated with several signaling pathways related to leukemogenesis and inflammation.

Palavras-chave

Myeloid neoplasms; Leukemia; FMNL1

Financiador do resumo

Support by FAPESP, CNPq, and CAPES