title: Mutation of the receptor tyrosine phosphatase PTPRC (CD45) in T-cell acute lymphoblastic leukemia.
abstract: The protein tyrosine phosphatase CD45, encoded by the PTPRC gene, is well known as a regulator of B- and T-cell receptor signaling. In addition, CD45 negatively regulates JAK family kinases downstream of cytokine receptors. Here, we report the presence of CD45 inactivating mutations in T-cell acute lymphoblastic leukemia. Loss-of-function mutations of CD45 were detected in combination with activating mutations in IL-7R, JAK1, or LCK, and down-regulation of CD45 expression caused increased signaling downstream of these oncoproteins. Furthermore, we demonstrate that down-regulation of CD45 expression sensitizes T cells to cytokine stimulation, as observed by increased JAK/STAT signaling, whereas overexpression of CD45 decreases cytokine-induced signaling. Taken together, our data identify a tumor suppressor role for CD45 in T-cell acute lymphoblastic leukemia.
authors.affiliation: Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Michaël
authors.initials: M
authors.lastname: Porcu
authors.forename: Maria
authors.initials: M
authors.lastname: Kleppe
authors.forename: Valentina
authors.initials: V
authors.lastname: Gianfelici
authors.forename: Ellen
authors.initials: E
authors.lastname: Geerdens
authors.forename: Kim
authors.initials: K
authors.lastname: De Keersmaecker
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Barbara
authors.initials: B
authors.lastname: Cauwelier
authors.forename: Anne
authors.initials: A
authors.lastname: Uyttebroeck
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D050791:STAT Transcription Factors; D053612:Janus Kinases; D017493:Leukocyte Common Antigens