ELMO1 Is Upregulated in AML CD34+ Stem/Progenitor Cells, Mediates Chemotaxis and Predicts Poor Prognosis in Normal Karyotype AML

Capala, Marta E.; Vellenga, Edo; Schuringa, Jan Jacob

doi:10.1371/journal.pone.0111568

Cited by 12 publications

(14 citation statements)

References 41 publications

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“…Co-cultures treated with 20μM and 40μM concentration of NSC proliferated significantly less already at week 2 of the co-culture and at week 3 cells treated with 40μM NSC ceased to grow ( Fig 1F ). This indicated that primary BCR-ABL-expressing cells are highly dependent on RAC signaling, which is in direct agreement with our previous findings [ 40 ]. Subsequently, we wondered whether also primary BC CML cells are dependent more on RAC2 than RAC1 expression.…”

Section: Resultssupporting

confidence: 93%

Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2

Capala¹,

Maat²,

Bonardi³

et al. 2015

PLoS ONE

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Leukemic stem cells (LSCs) reside within bone marrow niches that maintain their relatively quiescent state and convey resistance to conventional treatment. Many of the microenvironmental signals converge on RAC GTPases. Although it has become clear that RAC proteins fulfill important roles in the hematopoietic compartment, little has been revealed about the downstream effectors and molecular mechanisms. We observed that in BCR-ABL-transduced human hematopoietic stem/progenitor cells (HSPCs) depletion of RAC2 but not RAC1 induced a marked and immediate decrease in proliferation, progenitor frequency, cobblestone formation and replating capacity, indicative for reduced self-renewal. Cell cycle analyses showed reduced cell cycle activity in RAC2-depleted BCR-ABL leukemic cobblestones coinciding with an increased apoptosis. Moreover, a decrease in mitochondrial membrane potential was observed upon RAC2 downregulation, paralleled by severe mitochondrial ultrastructural malformations as determined by automated electron microscopy. Proteome analysis revealed that RAC2 specifically interacted with a set of mitochondrial proteins including mitochondrial transport proteins SAM50 and Metaxin 1, and interactions were confirmed in independent co-immunoprecipitation studies. Downregulation of SAM50 also impaired the proliferation and replating capacity of BCR-ABL-expressing cells, again associated with a decreased mitochondrial membrane potential. Taken together, these data suggest an important role for RAC2 in maintaining mitochondrial integrity.

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Section: Resultssupporting

confidence: 93%

Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2

Capala¹,

Maat²,

Bonardi³

et al. 2015

PLoS ONE

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“…The analysis of microarray data exhibited significant correlation of the expression of DOCK1 with that of HIF-1α and CXCR4 in our cohort (data not shown). This was consistent with previous study in which knock down of ELMO1 , the partner gene of DOCK1 , resulted in reduced chemotaxis of leukemia cells [ 3 ].…”

Section: Discussionsupporting

confidence: 93%

“…DOCK1 is known to interact physically with ELMO1, a mediator of chemotaxis in AML, with an implication in cell migration [ 2 , 3 ]. We reasoned that the adverse effect of higher DOCK1 expression in prognosis might be mediated by this axis.…”

Section: Resultsmentioning

confidence: 99%

“…The proteins in DOCK-A and B subgroups contain a terminal domain that allows binding of the adaptor protein ELMO (Engulfment and Motility) to promote efficient GEF activity [ 2 ]. Knocking down ELMO1 impairs long-term expansion of leukemic cell lines and depletion of ELMO1 in human CD34 + cells inhibit proliferation, possibly through the inhibition of ELMO-Rac axis [ 3 ]. The DOCK proteins are involved in several diseases including cancers, and disorders in the immune and central nervous systems [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

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High expression of dedicator of cytokinesis 1 (DOCK1) confers poor prognosis in acute myeloid leukemia

Lee

Chiu

et al. 2017

Oncotarget

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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.

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“…One of the characteristics of leukemia cells is invasion to other organs. Cytoskeletal proteins have an important role in AML cell migration ( 21 ). EPS8 is an important regulator of the cytoskeleton and is reported to be related to the migration and invasion of many solid tumours by regulating MMP9, E-cadherin and N-cadherin ( 7 ).…”

Section: Discussionmentioning

confidence: 99%

EPS8 regulates proliferation, apoptosis and chemosensitivity in BCR-ABL positive cells via the BCR-ABL/PI3K/AKT/mTOR pathway

et al. 2017

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Although the introduction of tyrosine kinase inhibitors greatly improved the survival of patients with chronic myeloid leukemia (CML), drug resistance remains a problem. Thus, mechanism-based novel therapeutic targets warrant exploration. Recently, epidermal growth factor receptor kinase substrate 8 (EPS8), which has been identified as an oncogene and plays an important role in a broad spectrum of solid tumours, was reported to be related to poor prognosis or chemoresistance in acute leukemia patients. However, its role in CML remains unclear. In the present study, using q-RT-PCR, we demonstrated that CML patients expressed a higher level of EPS8 mRNA in bone marrow mononuclear cells than healthy controls. Then, to determine the effect of EPS8 on the biological functions of CML cells, EPS8 expression was knocked down in the human CML cell line K562. Reduced proliferation, increased apoptosis, impaired adhesion and migration were observed in K562 cells after EPS8 silencing. Notably, attenuation of EPS8 increased chemosensitivity both in imatinib-sensitive K562 cells and in the imatinib-resistant murine BCR-ABL+ 32D-p210BCR/ABL-T315I cells. Mechanistically, knockdown of EPS8 downregulated p-BCR/ABL and its downstream AKT/mTOR signalling pathway. Finally, knockdown of EPS8 attenuated K562 cell proliferation in BALB/c nude mice. These data indicated that EPS8 regulated the proliferation, apoptosis and chemosensitivity in BCR-ABL positive cells via the BCR-ABL/PI3K/AKT/mTOR pathway. Targeting EPS8 alone or combined with a tyrosine kinase inhibitor may be a promising alternative therapeutic strategy.

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ELMO1 Is Upregulated in AML CD34+ Stem/Progenitor Cells, Mediates Chemotaxis and Predicts Poor Prognosis in Normal Karyotype AML

Cited by 12 publications

References 41 publications

Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2

Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2

High expression of dedicator of cytokinesis 1 (DOCK1) confers poor prognosis in acute myeloid leukemia

EPS8 regulates proliferation, apoptosis and chemosensitivity in BCR-ABL positive cells via the BCR-ABL/PI3K/AKT/mTOR pathway

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