Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKC  subversion induces up-regulation of PKC II expression in B lymphocytes

Nakagawa, Rinako; Vukovic, Milica; Tarafdar, Anuradha; Cosimo, Emilio; Dunn, Kirsty; McCaig, Alison M.; Holroyd, Ailsa K.; McClanahan, Fabienne; Ramsay, Alan G.; Gribben, John G.; Michie, Alison M.

doi:10.3324/haematol.2014.112276

Cited by 8 publications

(28 citation statements)

References 51 publications

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“…PKC is rarely mutated in haematological malignancies. Nevertheless, it has been shown that its associated signalling is critical for leukemic cell growth and disease progression [21][22][23][24] and also for chemoresistance [19,20,25]. In fact, we found that very dissimilar leukemic cell lines (B-ALL, T-ALL, CML, multiple myeloma), were severely affected by a 2 h treatment with 40 µM HKPS, a chimeric peptide able to penetrate cells and inhibit PKC activity [29].…”

Section: Discussionmentioning

confidence: 81%

“…Additionally, PKCα and PKC-βII activity has been associated with cell survival and proliferation in AML and CLL, respectively [21][22][23]. The same authors showed that modulation of PKCα function play a role in CLL development [23,24]. Although classic PKC isoforms have been frequently implicated in leukemic growth, other "novel" isoforms (δ and ε) have also been reported [25].…”

Section: Introductionmentioning

confidence: 97%

“…More recently, it was shown that PKCα activity promotes BCL-2 phosphorylation and chemoresistance in ALL [19], and by inducing RACK1 over-expression PKCα is responsible of T-ALL resistance to vincristine and prednisone [20]. Additionally, PKCα and PKC-βII activity has been associated with cell survival and proliferation in AML and CLL, respectively [21][22][23]. The same authors showed that modulation of PKCα function play a role in CLL development [23,24].…”

Section: Introductionmentioning

confidence: 99%

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Dual Targeting of Stromal Cell Support and Leukemic Cell Growth by a Peptidic PKC Inhibitor Shows Effectiveness against B-ALL

Ruiz-Aparicio

Vanegas

Uribe

et al. 2020

IJMS

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Mesenchymal stem cells (MSC) favour a scenario where leukemic cells survive. The protein kinase C (PKC) is essential to confer MSC support to leukemic cells and may be responsible for the intrinsic leukemic cell growth. Here we have evaluated the capacity of a chimeric peptide (HKPS), directed against classical PKC isoforms, to inhibit leukemic cell growth. HKPS was able to strongly inhibit viability of different leukemic cell lines, while control HK and PS peptides had no effect. Further testing showed that 30% of primary samples from paediatric B-cell acute lymphoblastic leukaemia (B-ALL) were also strongly affected by HKPS. We showed that HKPS disrupted the supportive effect of MSC that promote leukemic cell survival. Interestingly, ICAM-1 and VLA-5 expression increased in MSC during the co-cultures with B-ALL cells, and we found that HKPS inhibited the interaction between MSC and B-ALL cells due to a reduction in the expression of these adhesion molecules. Of note, the susceptibility of B-ALL cells to dexamethasone increased when MSC were treated with HKPS. These results show the relevance of these molecular interactions in the leukemic niche. The use of HKPS may be a new strategy to disrupt intercellular communications, increasing susceptibility to therapy, and at the same time, directly affecting the growth of PKC-dependent leukemic cells.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Dual Targeting of Stromal Cell Support and Leukemic Cell Growth by a Peptidic PKC Inhibitor Shows Effectiveness against B-ALL

Ruiz-Aparicio

Vanegas

Uribe

et al. 2020

IJMS

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“…To address the role of mTOR inhibition in CLL progression, in vitro -generated leukemic cells or mice with established leukemia from a poor-prognostic, proliferating CLL-like mouse model were treated with rapamycin or AZD8055 (23, 27). Analysis of mTOR substrate activation in PKCα-KR-expressing (CLL-like) or MIEV (empty vector control) cells revealed elevated phosphorylation of downstream mTOR targets (S6 S235/236 , AKT S473 ) in CLL-like cells (Figure 3D).…”

Section: Resultsmentioning

confidence: 99%

AKT/mTORC2 Inhibition Activates FOXO1 Function in CLL Cells Reducing B-Cell Receptor-Mediated Survival

Cosimo

Tarafdar

Moles

et al. 2019

Clinical Cancer Research

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Purpose To determine whether inhibition of mechanistic target of rapamycin (mTOR) kinase-mediated signaling represents a valid therapeutic approach for chronic lymphocytic leukemia (CLL). Experimental Design Stratification of mTOR activity was carried out in primary CLL patient samples and an aggressive CLL-like mouse model. The potency of dual mTOR inhibitor AZD8055 to induce apoptosis in primary CLL cells was assessed in the presence/absence of B cell receptor (BCR) ligation. Furthermore, we addressed the molecular and functional impact of dual mTOR inhibition in combination with BTK inhibitor ibrutinib. Results Differential regulation of basal mTORC1 activity was observed in poor prognostic CLL samples, with elevated p4EBP1T37/46 and decreased p70S6 kinase activity, suggesting that dual mTORC1/2 inhibitors may exhibit improved response in poor prognostic CLL compared with rapalogs. AZD8055 treatment of primary CLL cells significantly reduced CLL survival in vitro compared with rapamycin, preferentially targeting poor prognostic subsets and overcoming BCR-mediated survival advantages. Furthermore, AZD8055, and clinical analog AZD2014, significantly reduced CLL tumor load in mice. AKT substrate FOXO1, while overexpressed in CLL cells of poor prognostic patients in LN biopsies, peripheral CLL cells, and mouse-derived CLL-like cells, appeared to be inactive. AZD8055 treatment partially reversed FOXO1 inactivation downstream of BCR crosslinking, significantly inhibiting FOXO1T24 phosphorylation in an mTORC2-AKT-dependent manner, to promote FOXO1 nuclear localization, activity and FOXO1-mediated gene regulation. FOXO1 activity was further significantly enhanced on combining AZD8055 with ibrutinib. Conclusions Our studies demonstrate that dual mTOR inhibitors show promise as future CLL therapies, particularly in combination with ibrutinib.

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“…While ENZ failed to show significant clinical benefit in solid tumors, it has showed promising results as a single agent in a variety of pretreated B-cell malignancies, including Waldenström macroglobulinemia (overall response rate (ORR) of 38.1%) [18] and follicular lymphoma (ORR of 26.4% including 2 complete responses) [19]. Targeting PKC␤ with ENZ and other novel PKC␤ inhibitors, such as AEB071, continues to be evaluated in CLL and DLBCL, in order to elucidate the exact mechanism of action, and to find the best synergistic combination [20,21] (www.clinicaltrials.gov; Identifier: NCT01854606). In this study, we profile the sensitivity of seven B-ALL cell lines to ENZ, and detail the underlying mechanism of action.…”

Section: Introductionmentioning

confidence: 97%

Disruption of pre-B-cell receptor signaling jams the WNT/β-catenin pathway and induces cell death in B-cell acute lymphoblastic leukemia cell lines

et al. 2015

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Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKC subversion induces up-regulation of PKC II expression in B lymphocytes

Cited by 8 publications

References 51 publications

Dual Targeting of Stromal Cell Support and Leukemic Cell Growth by a Peptidic PKC Inhibitor Shows Effectiveness against B-ALL

Dual Targeting of Stromal Cell Support and Leukemic Cell Growth by a Peptidic PKC Inhibitor Shows Effectiveness against B-ALL

AKT/mTORC2 Inhibition Activates FOXO1 Function in CLL Cells Reducing B-Cell Receptor-Mediated Survival

Disruption of pre-B-cell receptor signaling jams the WNT/β-catenin pathway and induces cell death in B-cell acute lymphoblastic leukemia cell lines

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