Bruton's Tyrosine Kinase Cooperates with the B Cell Linker Protein SLP-65 as a Tumor Suppressor in Pre-B Cells

Kersseboom, Rogier; Middendorp, Sabine; Dingjan, Gemma M.; Dahlenborg, Katarina; Reth, Michael; Jumaa, Hassan; Hendriks, Rudolf W.

doi:10.1084/jem.20030615

Cited by 97 publications

(134 citation statements)

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“…BLNK -/-Btk -/-mice were affected with this malignancy at a higher rate (6/21, or 29%) by 16 wk (Fig. 4A-D), consistent with previous studies [23,30]. A similar frequency of BLNK -/-PLCc2 -/-mice (4/13, or 31%) became visibly ill or died by 16 wk (Fig.…”

Section: Differential Roles For Btk and Plcc2 In Pre-b Cell Tumor Supsupporting

confidence: 90%

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Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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The pre-BCR and the BCR regulate B cell development via a signalosome nucleated by the adaptor protein B cell linker protein (BLNK). Formation of this complex facilitates activation of phospholipase C (PLC) c2 by Bruton's tyrosine kinase (Btk). To determine whether Btk and PLCc2 also have separate functions, we generated Btk -/-PLCc2 -/-mice. They demonstrated a block in development at the pre-B stage and increased pre-BCR surface expression. This phenotype was more severe than that of Btk -/-or PLCc2 -/-mice. Although both Btk and PLCc2 were required for proliferation of splenic B cells in response to BCR cross-linking, they contributed differently to anti-IgM-induced phosphorylation of ERK. Btk -/-and PLCc2 -/-mice each had a reduced frequency of Igk-expressing B cells and impaired migration of pre-B cells towards stromal cellderived factor 1. However, the increase in pre-B cell malignancy that occurs in BLNK -/-mice in the absence of Btk was not observed in the absence of PLCc2. Thus, Btk and PLCc2 act both in concert and independently throughout B cell development. IntroductionSignals from the B cell antigen receptor (BCR) regulate multiple stages of B lymphopoiesis [1]. In pre-B cells, the pre-BCR signals for proliferation, allelic exclusion of the IgH locus, down-regulation of VpreB and k5 expression, and light chain rearrangement. The pre-BCR is predominantly intracellular and is believed to signal in a ligand-independent manner. The BCR is first expressed on the surface of immature B cells. Antigen encounter at this stage results in negative selection via deletion, anergy, or receptor editing. A tonic BCR signal is required for differentiation beyond the T2 stage in the periphery and survival of mature B cells. Mature B cells proliferate and differentiate upon stimulation with foreign antigen in the appropriate context. BCR and pre-BCR signaling is mediated by a signalosome composed of Syk, Bruton's tyrosine kinase (Btk), B cell linker protein (BLNK; also known as SLP65 and BASH), and phospholipase C (PLC) c2 [2-4]. Receptor cross-linking activates Syk, which phosphorylates the adaptor protein BLNK. Btk and PLCc2 bind to phosphorylated BLNK via their SH2 domains. Btk then phosphorylates and activates PLCc2, resulting in changes in intracellular Ca 2+ and the activation of protein kinase Cb. Btk can also mediate BCR-stimulated Ca 2+ flux [5] and B cell development [6] independently of its catalytic activity. Btk acts as an adaptor to recruit and activate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) [5], which produces the substrate for PLCc2. Thus, Btk signals through PLCc2 directly, by phosphorylation, and indirectly, by increasing substrate availability.Loss of Btk function causes the human immunodeficiency X-linked agammaglobulinemia (XLA) [7,8], which is characterized by a block in B cell development at the pre-B stage. A similar disease results from

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Section: Differential Roles For Btk and Plcc2 In Pre-b Cell Tumor Supsupporting

confidence: 90%

“…Some BLNK -/-mice develop pre-B lymphoma [21]. This occurs at a higher rate in the absence of Btk [23], indicating a BLNK-independent role for Btk as a tumor suppressor.…”

Section: Introductionmentioning

confidence: 99%

Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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“…Previous data show that up to 15-fold overexpression of human BTK in BtkÀ/À mice actually functions as tumor suppressor gene. 53,54 This level of expression far exceeds what is reached with EFS and CD19 promoters but is lower than that with the viral SFFV promoter. With this promoter, levels of BTK expression were very high and 80% of mice developed erythromyeloid proliferations within a few weeks after transplantation.…”

Section: Discussionmentioning

confidence: 93%

Correction of B-cell development in Btk-deficient mice using lentiviral vectors with codon-optimized human BTK

Baert

Pike-Overzet

et al. 2010

Leukemia

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X-linked agammaglobulinemia (XLA) is the most common primary immunodeficiency (PID) in man and caused by mutations in the Bruton's tyrosine kinase (BTK) gene. XLA is characterized by a B-cell differentiation arrest in bone marrow, absence of mature B cells and immunoglobulins (Igs), and recurrent bacterial infections. We used self-inactivating lentiviral vectors expressing codon-optimized human BTK under the control of three different ubiquitous or B cell-specific promoters. BtkÀ/À mice engrafted with transduced cells showed correction of both precursor B-cell and peripheral B-cell development. Lentiviral vectors containing the wildtype BTK sequence did not correct the phenotype. All treated mice with codon-optimized BTK exhibited the recovery of B1 cells in the peritoneal cavity, and of serum IgM and IgG3 levels. Calcium mobilization responses upon B-cell receptor stimulation as well as in vivo responses to T cell-independent antigens were restored. Viral promoters overexpressing BTK 4100-fold above normal resulted in erythro-myeloid proliferations independent of insertional mutagenesis. However, transplantation into secondary BtkÀ/À recipients using cellular promoters resulted in functional restoration of peripheral B cells and IgM levels, without any adverse effects. In conclusion, transduction of human BTK corrects B-cell development and antigen-specific antibody responses in BtkÀ/À mice, thus indicating the feasibility of lentiviral gene therapy for XLA, provided that BTK expression does not vastly exceed normal levels.

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“…In the absence of SLP65, B cell development is arrested at the pro-B to pre-B cell transition (Minegishi et al, 1999;Pappu et al, 1999), which parallels complete breakdown of (pre-) B cell receptor signaling in SLP65-deficient B cells (Ishiai et al, 1999;Pappu et al, 1999;Hayashi et al, 2003). While one study reported normal expression of SLP65 in childhood acute lymphoblastic leukemia (Imai et al, 2004), recent work by us and others Hayashi et al, 2003;Jumaa et al, 2003;Kersseboom et al, 2003;Klein et al, 2004) indicated a role of SLP65 as a tumor suppressor in human and murine leukemia derived from pre-B cells. Based on these findings, we investigated (i.)…”

Section: Introductionmentioning

confidence: 97%

The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells

et al. 2006

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SLP65 represents a critical component in (pre-) B cell receptor signal transduction but is compromised in a subset of pre-B cell-derived acute lymphoblastic leukemia. Based on these findings, we investigated (i.) whether SLP65-deficiency also occurs in mature B cell-derived lymphoma and (ii.) whether SLP65-deficient B cell lymphoma cells use an alternative B cell receptor signaling pathway in the absence of SLP65. Indeed, expression of SLP65 protein was also missing in a fraction of B cell lymphoma cases. While SLP65 is essential for B cell receptor-induced Ca 2 þ mobilization in normal B cells, B cell receptor engagement in SLP65-deficient as compared to SLP65-reconstituted B cell lymphoma cells resulted in an accelerated yet shortlived Ca 2 þ -signal. B cell receptor engagement of SLP65-deficient lymphoma cells involves SRC kinase activation, which is critical for B cell receptor-dependent Ca 2 þ -mobilisation in the absence but not in the presence of SLP65. As shown by RNA interference, the SRC kinase LYN is required for B cell receptor-induced Ca 2 þ release in SLP65-deficient B cell lymphoma cells but dispensable after SLP65-reconstitution. B cell receptor engagement in SLP65-deficient B cell lymphoma cells also resulted in tyrosine-phosphorylation of the proliferation-and survival-related MAPK1 and STAT5 molecules, which was sensitive to silencing of the SRC kinase LYN. Inhibition of SRC kinase activity resulted in growth arrest and cell death specifically in SLP65-deficient lymphoma cells. These findings indicate that LYN can short-circuit conventional B cell receptor signaling in SLP65-deficient B cell lymphoma cells and thereby promote activation of survival and proliferationrelated molecules.

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Bruton's Tyrosine Kinase Cooperates with the B Cell Linker Protein SLP-65 as a Tumor Suppressor in Pre-B Cells

Cited by 97 publications

References 30 publications

Btk and phospholipase Cγ2 can function independently during B cell development

Btk and phospholipase Cγ2 can function independently during B cell development

Correction of B-cell development in Btk-deficient mice using lentiviral vectors with codon-optimized human BTK

The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells

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