title: Y-box-binding protein 1 contributes to IL-7-mediated survival signaling in B-cell precursor acute lymphoblastic leukemia.
abstract: Y-box-binding protein 1 (YB-1) is a regulatory protein that is associated with drug resistance and relapse in solid tumors. As YB-1 mediates some of its activity through growth factor receptor signaling dysregulation, the present study compared the expression of YB-1 and interleukin 7 (IL-7) receptor α (IL-7Rα) in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) and normal BCP cells. The expression levels of IL-7Rα and YB-1 were higher in relapsed vs. diagnostic samples of primary BCP ALL; however, co-expression was also observed in a minor BCP cell population in samples from healthy donors. Functional crosstalk between YB-1 and IL-7R was detected: Overexpression of YB-1 increased surface levels of IL-7R in B cells, and the stimulation of BCP ALL cell lines and primary samples by IL-7 activated YB-1 by phosphorylation at S102 in a phosphatidylinositol 3-kinase-independent and MEK1/2-dependent manner. Targeted knockdown of YB-1 reduced IL-7-mediated protection against rapamycin, and an inhibitor of MEK1/2 potentiated rapamycin-mediated killing in the presence of IL-7. These data establish a novel link between two well-characterized pro-survival factors in acute leukemia, and suggest that YB-1 inhibition may represent a novel therapeutic strategy for increasing sensitivity to chemotherapy in patients with refractory acute B-cell leukemia.
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Kariminia
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Ivison
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Vivian M
authors.initials: VM
authors.lastname: Leung
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Susanna
authors.initials: S
authors.lastname: Sung
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Couto
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Rozmus
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Nina
authors.initials: N
authors.lastname: Rolf
authors.affiliation: Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, AB T2N 4N1, Canada.
authors.forename: Aru
authors.initials: A
authors.lastname: Narendran
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Dunn
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Gregor S D
authors.initials: GS
authors.lastname: Reid
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Schultz
keywords: Y-box-binding protein 1; acute lymphoblastic leukemia; interleukin-7; relapse