title: Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy.
abstract: Bone marrow (BM) provides chemoprotection for acute lymphoblastic leukemia (ALL) cells, contributing to lack of efficacy of current therapies. Integrin alpha4 (alpha4) mediates stromal adhesion of normal and malignant B-cell precursors, and according to gene expression analyses from 207 children with minimal residual disease, is highly associated with poorest outcome. We tested whether interference with alpha4-mediated stromal adhesion might be a new ALL treatment. Two models of leukemia were used, one genetic (conditional alpha4 ablation of BCR-ABL1 [p210(+)] leukemia) and one pharmacological (anti-functional alpha4 antibody treatment of primary ALL). Conditional deletion of alpha4 sensitized leukemia cell to nilotinib. Adhesion of primary pre-B ALL cells was alpha4-dependent; alpha4 blockade sensitized primary ALL cells toward chemotherapy. Chemotherapy combined with Natalizumab prolonged survival of NOD/SCID recipients of primary ALL, suggesting adjuvant alpha4 inhibition as a novel strategy for pre-B ALL.
authors: Department of Pediatrics, Division of Hematology and Oncology, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA.
authors: Yao-Te
authors: YT
authors: Hsieh
authors: Eun Ji
authors: EJ
authors: Gang
authors: Huimin
authors: H
authors: Geng
authors: Eugene
authors: E
authors: Park
authors: Sandra
authors: S
authors: Huantes
authors: Doreen
authors: D
authors: Chudziak
authors: Katrin
authors: K
authors: Dauber
authors: Paul
authors: P
authors: Schaefer
authors: Carlton
authors: C
authors: Scharman
authors: Hiroyuki
authors: H
authors: Shimada
authors: Seyedmehdi
authors: S
authors: Shojaee
authors: Lars
authors: L
authors: Klemm
authors: Reshmi
authors: R
authors: Parameswaran
authors: Mignon
authors: M
authors: Loh
authors: Eun-Suk
authors: ES
authors: Kang
authors: Hong Hoe
authors: HH
authors: Koo
authors: Wolf-Karsten
authors: WK
authors: Hofmann
authors: Jacob
authors: J
authors: Andrade
authors: Gay M
authors: GM
authors: Crooks
authors: Cheryl L
authors: CL
authors: Willman
authors: Markus
authors: M
authors: Müschen
authors: Thalia
authors: T
authors: Papayannopoulou
authors: Nora
authors: N
authors: Heisterkamp
authors: Halvard
authors: H
authors: Bönig
authors: Yong-Mi
authors: YM
authors: Kim
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002648:Child; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D019426:Integrases / Q000378:metabolism; D039441:Integrin alpha4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D000069442:Natalizumab; D018365:Neoplasm, Residual / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab; D012333:RNA, Messenger; D039441:Integrin alpha4; D016044:Fusion Proteins, bcr-abl; C045073:Cre recombinase; D019426:Integrases