title: Crosstalk between ROR1 and the Pre-B cell receptor promotes survival of t(1;19) acute lymphoblastic leukemia.
abstract: We report that t(1;19) ALL cells universally exhibit expression of and dependence on the cell surface receptor ROR1. We further identify t(1;19) ALL cell sensitivity to the kinase inhibitor dasatinib due to its inhibition of the pre-B cell receptor (pre-BCR) signaling complex. These phenotypes are a consequence of developmental arrest at an intermediate/late stage of B-lineage maturation. Additionally, inhibition of pre-BCR signaling induces further ROR1 upregulation, and we identify distinct ROR1 and pre-BCR downstream signaling pathways that are modulated in a counterbalancing manner-both leading to AKT phosphorylation. Consistent with this, AKT phosphorylation is transiently eliminated after dasatinib treatment, but is partially restored following dasatinib potentiation of ROR1 expression. Consequently, ROR1 silencing accentuates dasatinib killing of t(1;19) ALL cells.
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA. tynerj@ohsu.edu
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Bicocca
authors.forename: Bill H
authors.initials: BH
authors.lastname: Chang
authors.forename: Behzad Kharabi
authors.initials: BK
authors.lastname: Masouleh
authors.forename: Markus
authors.initials: M
authors.lastname: Muschen
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
mesh_terms: D002878:Chromosomes, Human, Pair 1; D002888:Chromosomes, Human, Pair 19; D000069439:Dasatinib; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D010766:Phosphorylation; D054420:Pre-B Cell Receptors / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000502:physiology*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D014178:Translocation, Genetic
chemical_list: D054420:Pre-B Cell Receptors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D051057:Proto-Oncogene Proteins c-akt; D000069439:Dasatinib