Abstract
DOCK family genes encode evolutionarily conserved guanine nucleotide exchange factors for Rho GTPase involving multiple biological functions. Yet the patterns and prognostic significance of their expression in acute myeloid leukemia (AML) remain unexplored. Here we analyzed the expression patterns of 11 DOCK family genes in AML cells based on the array data of 347 patients from our cohort and several other published datasets. We further focused on the implications of the expression of DOCK1 since it was the only one in DOCK family to be associated with survival. Physiological functions and biological pathways associated with DOCK1 were identified using bioinformatics approaches. With a median follow up of 57 months, higher DOCK1 expression was associated with shorter disease free and overall survival. The finding could be validated by two independent cohorts. Multivariate analysis showed higher DOCK1 expression as a strong independent unfavorable prognostic factor. Higher DOCK1 expression was closely associated with older age, higher platelet and peripheral blast counts, intermediate-risk cytogenetics, FLT3-ITD, MLL-PTD and mutations in PTPN11, NPM1, RUNX1, ASXL1 and DNMT3A. Functional enrichment analysis suggested the association of DOCK1 overexpression with several key physiological pathways including cell proliferation, motility, and chemotaxis. Therefore, we suggested that AML with higher DOCK1 expression showed characteristic clinical and biological features. DOCK1 expression is an important prognostic marker and a potential therapeutic target for the treatment of AML. Studies in large prospective cohorts are necessary to confirm our findings. Further mechanistic studies to delineate the role of DOCK1 in the leukemogenesis are warranted.
Highlights
The Dedicator of cytokinesis (DOCK) family protein is a novel class of guanine nucleotide exchange factors (GEF) for Rac GTPases of the Rho family, [1] and is known to involved in the regulation of actin cytoskeleton, cell motility, [2] as well as cell cycle, survival, gene expression, and tumorigenesis [1].There are 11 DOCK proteins (DOCK1 to DOCK11) in mammals, which are further classified into four subgroups according to the sequence similarity and domain organization
DOCK1 seemed to be exclusively abundant in hematopoietic stem cells (HSC)
While DOCK proteins have pleiotropic functions in immunity, neurology, cytokinesis, and motility, their functions in hematopoietic system and prognostic significance in acute myeloid leukemia (AML) are totally unknown. We addressed these questions by analyzing the expression patterns of the 11 DOCK member genes in normal hematopoietic and AML cells
Summary
The Dedicator of cytokinesis (DOCK) family protein is a novel class of guanine nucleotide exchange factors (GEF) for Rac GTPases of the Rho family, [1] and is known to involved in the regulation of actin cytoskeleton, cell motility, [2] as well as cell cycle, survival, gene expression, and tumorigenesis [1].There are 11 DOCK proteins (DOCK1 to DOCK11) in mammals, which are further classified into four subgroups (denoted as A to D) according to the sequence similarity and domain organization. The DOCK proteins are involved in several diseases including cancers, and disorders in the immune and central nervous systems [1]. Despite the protean functions of DOCK proteins in cancers and hematopoiesis, their roles in acute myeloid leukemia (AML) have not been explored. We first screened the expression levels of DOCK family genes in a cohort of AML patients. The members with at least modest expression in AML were selected to test their prognostic significance in ours and the other two independent cohorts. We found that expression level of DOCK1 but not the other members harbored prominent prognostic significance in both ours and other independent cohorts of AML patients. Bioinformatics analyses were performed to identify potential pathway and function of DOCK1 in AML
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