miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells

Lechman, Eric R.; Gentner, Bernhard; Ng, Stanley W.K.; Schoof, Erwin M.; Galen, Peter van; Kennedy, James A.; Nucera, Silvia; Ciceri, Fabio; Kaufmann, Kerstin B.; Takayama, Nobuki; Dobson, Stephanie M.; Trotman-Grant, Aaron C.; Krivdova, Gabriela; Elzinga, Janneke; Mitchell, Amanda; Nilsson, Björn; Hermans, Karin G.; Eppert, Kolja; Marke, René; Isserlin, Ruth; Voisin, Véronique; Bader, Gary D.; Zandstra, Peter W.; Golub, Todd R.; Ebert, Benjamin L.; Lu, Jun; Minden, Mark D.; Wang, Jean; Naldini, Luigi; Dick, John E.

doi:10.1016/j.ccell.2016.03.015

Cited by 97 publications

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“…miR-126 is located within intron 7 of a protein-coding gene known as Epithelial growth factor-like 7 (EGFL7) (3). Although we and others (2,4,5) have shown an important role for miR-126 in AML biology, we know of no studies that have been performed to understand the prognostic and functional implications of expression of its host gene, EGFL7, in AML.…”

Section: Egfl7 | Acute Myeloid Leukemia | Clinical Outcomementioning

confidence: 99%

Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia

Papaioannou

Shen

Nicolet

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial growth factor-like 7 (EGFL7) is a protein that is secreted by endothelial cells and plays an important role in angiogenesis. Although EGFL7 is aberrantly overexpressed in solid tumors, its role in leukemia has not been evaluated. Here, we report that levels of both EGFL7 mRNA and EGFL7 protein are increased in blasts of patients with acute myeloid leukemia (AML) compared with normal bone marrow cells. High EGFL7 mRNA expression associates with lower complete remission rates, and shorter event-free and overall survival in older (age ≥60 y) and younger (age <60 y) patients with cytogenetically normal AML. We further show that AML blasts secrete EGFL7 protein and that higher levels of EGFL7 protein are found in the sera from AML patients than in sera from healthy controls. Treatment of patient AML blasts with recombinant EGFL7 in vitro leads to increases in leukemic blast cell growth and levels of phosphorylated AKT. EGFL7 blockade with an anti-EGFL7 antibody reduced the growth potential and viability of AML cells. Our findings demonstrate that increased EGFL7 expression and secretion is an autocrine mechanism supporting growth of leukemic blasts in patients with AML. EGFL7 | acute myeloid leukemia | clinical outcomeA cute myeloid leukemia (AML) is a clonal hematopoietic disease characterized by the proliferation of immature blasts in the bone marrow (BM) and blood (1). Genetic alterations, including chromosomal translocations and deletions and gene mutations leading to aberrant downstream target gene expression, contribute to AML initiation and maintenance. Previously, our group demonstrated that increased miRNA-126-3p (miR-126) expression in patients with cytogenetically normal AML (CN-AML) correlated with shorter overall survival (OS). Furthermore, we found miR-126 to be essential for leukemia stem cell (LSC) homeostasis, and in vivo targeting of miR-126 in a patientderived xenograft model resulted in prolonged survival in secondary bone marrow transplant (BMT) recipients (2). miR-126 is located within intron 7 of a protein-coding gene known as Epithelial growth factor-like 7 (EGFL7) (3). Although we and others (2, 4, 5) have shown an important role for miR-126 in AML biology, we know of no studies that have been performed to understand the prognostic and functional implications of expression of its host gene, EGFL7, in AML.EGFL7 is a secreted protein of ∼30 kDa and plays an important physiological role in angiogenesis (6-8). Unlike other angiogenic factors (e.g., VEGF), physiological EGFL7 expression and function has been restricted mainly to the endothelial cells where it regulates survival, migration, and differentiation (6). Aberrant expression of EGFL7 has been shown to be involved in tumor growth and disease progression of several solid tumors, including hepatocellular carcinoma, malignant glioma, and breast, lung, and pancreatic cancers (9), but its role in hematopoietic malignancies is currently unknown. Therefore, we investigated the prognostic and biological function of EGFL7 expression in A...

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Section: Egfl7 | Acute Myeloid Leukemia | Clinical Outcomementioning

confidence: 99%

Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia

Papaioannou

Shen

Nicolet

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Blockade of the PD-1 pathway in mice also promotes killing of GSCs by NK cells division (132,133). Slow-growing tumor cells are important targets to prevent chemo-and radioresistance (20,55,132,133,(159)(160)(161). However, in the majority of molecularly targeted therapies, the targets of interest were selected based on highly expressed molecules found on a large fraction of tumor cells, such as the tyrosine kinase receptors, and their downstream signaling effectors (162)(163)(164).…”

Section: Molecular Pathways Implicated In Therapeutic Resistance Of Rmentioning

confidence: 99%

Overcoming therapeutic resistance in glioblastoma: the way forward

Osuka¹,

Meir²

2017

Journal of Clinical Investigation

378

283

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“…Therefore, studying of miR-126 dose responses may yield important insights into growth regulation in healthy and malignant hematopoiesis. 37,38 To further extend the power of FGB approaches, multiplexing of up to 12 populations can readily be achieved with the FGB-BC vector platform by mixing of FGB-BC color-coded cells derived from CD45.1 and CD45.2 murine cell lines for competitive in vitro tracking or transplantation into CD45.1xCD45.2 F1 mice. Importantly, in an independent study published in this issue of Molecular Therapy, Mohme et al 39 present an extended color-coding strategy based on a set of six lentiviral vectors expressing unique fluorescent proteins for the combinatorial transduction of cells with up to three fluorescent markers.…”

Section: Discussionmentioning

confidence: 99%

A Lentiviral Fluorescent Genetic Barcoding System for Flow Cytometry-Based Multiplex Tracking

et al. 2017

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miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells

Cited by 97 publications

References 0 publications

Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia

Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia

Overcoming therapeutic resistance in glioblastoma: the way forward

A Lentiviral Fluorescent Genetic Barcoding System for Flow Cytometry-Based Multiplex Tracking

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