Roles for phosphoinositide 3‐kinases, Bruton's tyrosine kinase, and Jun kinases in B lymphocyte chemotaxis and homing

Ortolano, Saida; Hwang, Il‐Young; Han, Sang‐Bae; Kehrl, John H.

doi:10.1002/eji.200535799

Cited by 52 publications

(40 citation statements)

References 51 publications

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“…This finding contrasts with two previous studies reporting either no change or decreased lymph node homing of WMN-treated B cells (7,16). These differing results could be due to the different time periods of WMN pretreatment and homing analysis among the three studies.…”

Section: Discussioncontrasting

confidence: 97%

“…We analyzed B cell homing 4 h posttransfer, whereas other investigators used 1.5 and 2 h (7, 16). Delayed homing is consistent with a report that WMNtreated B cells show reduced adhesion and increased rolling in high endothelial venules (16). It is also possible that WMN causes a delay in homing as well as a block in egress once cells enter the lymph node.…”

Section: Discussionsupporting

confidence: 91%

“…In B lymphocytes, PI3K inhibitors reduce chemotaxis to CXCL13 and DOCK2-independent homing, yet p110␥ is not required for these responses (6). In addition, class IA PI3K functions upstream and downstream of integrin activation in various cell types, providing a possible mechanism for regulating lymphocyte motility and polarization in the native environment of the lymph node (12)(13)(14)(15)(16).…”

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confidence: 99%

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Class IA Phosphoinositide 3-Kinase Modulates Basal Lymphocyte Motility in the Lymph Node

Matheu¹,

Deane²,

Parker

et al. 2007

The Journal of Immunology

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Recruitment of PI3K to the cell membrane is an indispensable step in normal lymphocyte proliferation and activation. In this study we identify PI3K as an important signaling molecule for maintaining basal T and B lymphocyte motility and homing in the intact lymph node. Pharmacological inhibition of PI3K catalytic isoforms exerted broad effects on basal lymphocyte motility, including changes in homing kinetics, localization of B cells within the lymph node, and reduced cell velocities. Lymphocytes deficient in either or both of the class IA PI3K regulatory subunits p85α and p85β also exhibited reduced velocities, with the magnitude of reduction depending upon both cell type and isoform specificity. B cells deficient in p85α exhibited gross morphological abnormalities that were not evident in cells treated with a PI3K inhibitor. Our results show, for the first time, that class IA PI3Ks play an important role in regulating basal lymphocyte motility and that p85α regulatory subunit expression is required to maintain B cell morphology in a manner independent of PI3K catalytic function. Moreover, we demonstrate distinct roles for catalytic domain function and class IA PI3K regulatory domain activity in lymphocyte motility, homing, and homeostatic localization of mature resting B cells.

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Section: Discussioncontrasting

confidence: 97%

Section: Discussionsupporting

confidence: 91%

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confidence: 99%

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Class IA Phosphoinositide 3-Kinase Modulates Basal Lymphocyte Motility in the Lymph Node

Matheu¹,

Deane²,

Parker

et al. 2007

The Journal of Immunology

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“…85 In addition to its role in BCR signaling, BTK is involved in signaling of other receptors related to B-cell migration and adhesion, such as chemokine receptors (CXCR4 and CXCR5) and adhesion molecules (integrins). [86][87][88] Ibrutinib, previously called PCI-32765, binds irreversibly to a cysteine residue (Cys-481) in the BTK kinase domain and inhibits BTK phosphorylation and its enzymatic activity. 89 Byrd et al 14 recently reported that single agent ibrutinib induces an overall response rate of 71% in CLL patients with relapsed or refractory disease and an additional 15% to 20% of patients had a partial response with lymphocytosis.…”

Section: Btk Inhibition In Cll and Other Lymphoid Malignanciesmentioning

confidence: 99%

Secondary mutations as mediators of resistance to targeted therapy in leukemia

Daver¹,

Cortes²,

Ravandi³

et al. 2015

Blood

121

110

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The advent of small molecule-based targeted therapy has improved the treatment of both acute and chronic leukemias. Resistance to small molecule inhibitors has emerged as a common theme. The most frequent mode of acquired resistance is the acquisition of point mutations in the kinase domain. FLT3 inhibitors have improved response rates in FLT3-mutated acute myeloid leukemia (AML). The occurrence of the ATP-binding site and activation loop mutations confers varying degrees of resistance to the individual FLT3 inhibitors. Second-generation FLT3 inhibitors such as crenolanib may overcome the resistance of these mutations. Furthermore, nonmutational mechanisms of resistance such as prosurvival pathways and bone marrow signaling may be upregulated in FLT3 inhibitor-resistant AML with secondary kinase domain mutations. More recently, point mutations conferring resistance to the Bruton tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia, arsenic trioxide in acute promyelocytic leukemia, and the BH3-mimetic ABT199 in lymphoma have been identified. In chronic myeloid leukemia, the emergence of tyrosine kinase domain mutations has historically been the dominant mechanism of resistance. The early identification of secondary point mutations and their downstream effects along with the development of second- or third-generation inhibitors and rationally designed small molecule combinations are potential strategies to overcome mutation-mediated resistance.

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“…19 In addition to its role in antigen-mediated BCR signaling, Btk is also involved in signaling of other cell-surface receptors, such as the CXCR4 and CXCR5 chemokine receptors and adhesion molecules (integrins) that are essential for B-cell trafficking and tissue homing. [20][21][22] PCI-32765 binds specifically and irreversibly to a cysteine residue in the Btk protein and inhibits Btk phosphorylation on Tyr 223 and consequently its enzymatic activity. 23 PCI-32765 shows encouraging clinical activity in patients with B-cell malignancies, particularly in CLL patients 24,25 ; this response is characterized by a rapid resolution of lymphadenopathy and/or organomegaly, accompanied by a transient surge in lymphocyte counts, presumably because of "mobilization" of tissue-resident CLL cells into the blood.…”

Section: Introductionmentioning

confidence: 99%

The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo

Ponader

Chen

Buggy

et al. 2012

Blood

585

544

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B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCRassociated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13 IntroductionChronic lymphocytic leukemia (CLL), the most common leukemia in western societies, is characterized by the accumulation of mature, CD5 ϩ CD23 ϩ monoclonal B lymphocytes in the blood, secondary lymphatic tissues, and the bone marrow. 1 Proliferating CLL cells, which account for approximately 0.1% to 1% of the CLL clone, 2 are typically found within microanatomical structures called proliferation centers or pseudofollicles, 3 where CLL cells interact with accessory cells (ie, stromal cells or T cells), thereby receiving survival and growth signals. 4 Such external signals from the leukemia microenvironment can supplement intrinsic oncogenic lesions, thereby promoting maintenance and expansion of the CLL clone. 3,5,6 Among the various external stimuli in the tissue microenvironments, B-cell receptor (BCR) activation and signaling, particularly in lymphatic tissues, 6 is a central pathologic mechanism, even though the precise mechanism of BCR stimulation and the nature of the antigen(s) that activate the BCRs remain obscure. 1,7 The most direct evidence for the importance of BCR signaling in CLL comes from recent comparative gene expression profiling (GEP) data that revealed BCR signaling as the most prominent pathway activated in CLL cells isolated from lymphatic tissues. 6 These GEP changes displayed remarkable similarity to GEP changes of CLL cells cocultured with monocyte-derived nurselike cells (NLC), 8 a system for studying the impact of the lymphatic tissue microenvironment in CLL in vitro. Additional evidence for the importance of BCR signaling in CLL comes from the observation that important CLL risk factors have functional links to the BCRs. The mutation status of the IgV H segments of the BCR distinguishes "mutated" (M-CLL) from "unmutated" CLL (U-CLL), with a low or high risk for disease progression, respectively, each accounting for approximately 50% of the patients. ZAP-70 is predominantly expressed in U-CLL cases, 9 and ZAP-70 expression is associated with enhanced BCR signaling. 10 Furthermore, CLL patients express restricted sets of BCRs, as determined by BCR sequencing. These BCRs have immunoglobulin (Ig) heavy-chain variable (V) gene sequences that are identical or stereotyped in subsets of patients, 11,12 suggesting that these BCR...

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Roles for phosphoinositide 3‐kinases, Bruton's tyrosine kinase, and Jun kinases in B lymphocyte chemotaxis and homing

Cited by 52 publications

References 51 publications

Class IA Phosphoinositide 3-Kinase Modulates Basal Lymphocyte Motility in the Lymph Node

Class IA Phosphoinositide 3-Kinase Modulates Basal Lymphocyte Motility in the Lymph Node

Secondary mutations as mediators of resistance to targeted therapy in leukemia

The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo

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