title: CD44 promotes chemoresistance in T-ALL by increased drug efflux.
abstract: T-Cell acute lymphoblastic leukemia is considered a largely curable disease in children; however, adult patients and children with refractory or relapsed disease have consistently poor outcomes. On the basis of our prior work highlighting CD44 as a marker of leukemia-initiating cells in animal models and because cancer stem cells are postulated to possess intrinsic resistance to conventional chemotherapy, we examined whether CD44 itself might play a role in mediating chemoresistance. We report here that in both genetically defined mouse models and human cell lines, CD44 expression is associated with chemoresistance, and that this effect is mediated in part through enhanced drug efflux. Interestingly, we also observed increased CD44 expression in residual blasts following standard induction chemotherapy, as compared with blasts from matched, pretherapy samples in a subset of pediatric patients undergoing minimal residual disease monitoring as part of a clinical trial. These findings support a functional role for CD44 in promoting chemotherapy resistance and suggest that targeting it directly or its relevant effector pathways may improve clinical responses in T-cell acute lymphoblastic leukemia.
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Hoofd
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Xuehai
authors.initials: X
authors.lastname: Wang
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Sonya
authors.initials: S
authors.lastname: Lam
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Jenkins
authors.affiliation: Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, WA.
authors.forename: Brent
authors.initials: B
authors.lastname: Wood
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Giambra
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada. Electronic address: aweng@bccrc.ca.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weng
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins