Oncogenic activation of the Lck protein accompanies translocation of the LCK gene in the human HSB2 T-cell leukemia.

Abstract

The tyrosine protein kinase p56ick transduces signals important for antigen-induced T-cell The lymphocyte-specific tyrosine protein kinase, p561ck, is expressed predominantly in T cells (13,30,53), where it is physically associated with the T-cell transmembrane proteins CD4 and CD8 (43,45,52). During T-cell activation, CD4 and CD8 bind to the major histocompatibility complex glycoprotein (class II or class I, respectively) on an antigen-presenting cell, bringing p56ick in close physical proximity to the T-cell receptor (16). Binding of the antigen-major histocompatibility complex to CD4 and the T-cell receptor subunits triggers the rapid phosphorylation of a set of T-cell proteins on tyrosine (20). pS6ick is thought to mediate some of these phosphorylations, because the addition of antibodies that cross-link cell surface CD4 induces tyrosine phosphorylation of p56ick and activates its phosphotransferase activity in vitro (19, 27).Genetic evidence likewise indicates that enhancement of T-cell activation by CD4 is mediated through pS6Ick. Deletion of the cytoplasmic domain of CD4 that binds p56 ck abrogates the ability of CD4 to enhance antigen-induced interleukin 2 (IL-2) production in CD4-dependent cells (18,33,46), and T cells expressing activated p56Ik are hypersensitive to stimulation through the T-cell receptor (1) while those lacking functional p56iCk are defective in inducing the transient increase in intracellular free calcium that accompanies antigenic stimulation through the T-cell receptor (48). Therefore, p56 Ck performs a pivotal role in T-cell activation.

Mutation of the receptor tyrosine phosphatase PTPRC (CD45) in T-cell acute lymphoblastic leukemia

“…We electroporated 9 T-ALL cell lines (ALL-SIL, HSB-2, HPB-ALL, MOLT-14, KE-37, SUP-T1, DND-41, P12-ichikawa, and TALL-1) with our siRNA library, and searched for siRNAs that significantly affected proliferation and survival of the cells. As expected, we identified ABL1 (NUP214-ABL1) as an essential kinase in ALL-SIL cells, 3 and LCK as an essential kinase in HSB-2 cells, 5 2 cell lines known to depend on these oncogenic kinases (supplemental Figure 1, available on the Blood Web site; see the Supplemental Materials link at the top of the online article). In addition, we identified tyrosine kinases that affected the proliferation and survival of several other T-ALL cell lines, the strongest hit being JAK1 in DND-41 cells (supplemental Figure 2).…”

“…Notably, these loss-of-function mutations all occurred together with activating mutations in pathways that are negatively regulated by CD45 (supplemental Table 1): CD45 R751* with a JAK1 Y652H gain-of-function mutant in patient TLE-28, 23 CD45 W764* with an activating IL-7R insertion in DND-41, and CD45 G863R with activating LCK mutations in HSB-2. 5,24 Furthermore, our data indicate that loss of CD45 renders the JAK/STAT signaling pathway more susceptible to activation, either by cytokines or by oncogenic proteins, and can affect cancer cell proliferation. Although CD45-inactivating mutations appear to be quite rare, it has been reported that CD45 expression is extremely low or undetectable in 3.7% of pediatric T-ALL and 12.9% of pediatric B-cell precursor ALL patients, 25 suggesting that additional mechanisms may exist for the inactivation of CD45.…”

“…1,2 T-ALL is also frequently characterized by the expression of constitutively activated tyrosine kinases, such as ABL1, LCK, JAK1, and JAK3. [3][4][5][6][7] Recently identified mutations in the IL-7 receptor ␣ (IL-7R) and deletions of the tyrosine phosphatase PTPN2 were also reported to affect tyrosine kinase signaling. [8][9][10] The genetic and functional data presented in this work now identify the tyrosine phosphatase CD45 as a new tumor suppressor gene in T-ALL.…”

Characterization of Interactions of Adapter Protein RAPL/Nore1B with RAP GTPases and Their Role in T Cell Migration

“…Cells Culture and Transfection-The HSB-2 T cell line was maintained in RPMI 1640-glutamine (Invitrogen BLR) sup-plemented with 10% fetal bovine serum and 2.4 mM glutamine at cell numbers between 1 and 4 ϫ 10 6 cells/ml (28). Transfections of HSB-2 cells with DNA or siRNA were carried out as previously described (20).…”

A Constitutively Active Lck Kinase Promotes Cell Proliferation and Resistance to Apoptosis through Signal Transducer and Activator of Transcription 5b Activation

“…In humans, the lck gene is located at a site of frequent chromosomal abnormalities associated with lymphomas (4). Aberrant Lck expression and kinase activity have also been implicated in the pathogenesis of both lymphoid and nonlymphoid malignancies (5,6). Like other Src family members, Lck kinase activity is negatively regulated by phosphorylation of a highly conserved tyrosine (Tyr 505 ) located near the carboxyl terminus of the protein (7).…”