The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease

Longo, Pablo G.; Laurenti, Luca; Gobessi, Stefania; Petlickovski, Aleksandar; Pelosi, Michele; Chiusolo, Patrizia; Sica, Simona; Leone, Giuseppe; Efremov, Dimitar G.

doi:10.1038/sj.leu.2404417

Cited by 135 publications

(188 citation statements)

References 60 publications

(70 reference statements)

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“…In line with the study by Longo et al (2007), CpG induced apoptosis in mutated CLL, and we observed that this could be completely prevented by simultaneous stimulation with CD40L ( Figure 4a). Next, drug sensitivity to bortezomib and fludarabine was measured in mutated and unmutated CLL cells after 72 h of CD40/TLR9 triggering.…”

Section: Resultssupporting

confidence: 92%

“…To more accurately mimic the in vivo LN microenvironment in which CLL cells proliferate, we stimulated CLL cells simultaneously with CD40L and CpG for 3 and 5 days, respectively. As shown before (Longo et al, 2007), stimulation with CpG only resulted in proliferation of unmutated, but not mutated, CLL cells (Figures 2a and b). The proliferating fraction on simultaneous CD40/TLR9 triggering was considerably larger than on triggering with either of the stimuli alone.…”

Section: Resultssupporting

confidence: 79%

“…Longo et al (2007), have shown that the TLR9 ligand CpG induces proliferation mainly in unmutated CLL cells, whereas mutated CLL cells undergo apoptosis. To more accurately mimic the in vivo LN microenvironment in which CLL cells proliferate, we stimulated CLL cells simultaneously with CD40L and CpG for 3 and 5 days, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…A dichotomy was observed in peripheral blood (PB) CLL cells from mutated versus unmutated CLL patients stimulated with CpG in vitro (Longo et al, 2007). CpG stimulation resulted in proliferation in the majority of unmutated CLL cells, whereas mutated CLL cells underwent apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

et al. 2010

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Chronic lymphocytic leukemia (CLL) cells circulating in peripheral blood (PB) differ from the leukemic fraction in lymph nodes (LNs) with respect to cell division and drug sensitivity. CD40 stimulation of PB CLL cells in vitro results in chemoresistance and provides a partial model for the LN microenvironment. The TLR9 ligand CpG induces proliferation in immunoglobulin variable heavychain-unmutated CLL, but apoptosis in immunoglobulin variable heavy-chain-mutated CLL. To juxtapose proliferative with antiapoptotic signals, we investigated the effects of CpG in the context of CD40 ligation in mutated versus unmutated CLL cells in this study. Prolonged CD40 ligation induced classical, followed by alternative nuclear factor-jB (NF-jB), activity in both subgroups, correlating with enhanced Bfl-1 and Bcl-X L levels, respectively. A dichotomy in NF-jB signaling occurred on combined CD40/TLR9 triggering. This induced declining p52 and Bcl-X L levels, and reversed chemoresistance only in mutated cells, whereas unmutated cells proliferated, maintained p52 and Bcl-X L and remained chemoresistant. The pivotal contribution of Bcl-X L to chemoresistance was shown by the BH3 mimetic ABT-737 and RNA interference. Finally, in ex vivo LN samples, p52, p65 and Bcl-X L levels were highly expressed, corroborating the in vitro findings. Thus, a distinction in NF-jB activation and drug susceptibility in mutated versus unmutated (LN-like) CLL cells was uncovered, which was causally linked to Bcl-X L levels.

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

et al. 2010

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“…[3][4][5] This kinase is also activated in response to many other microenvironmental stimuli that increase leukemic cell survival or induce proliferation, including CXCL12, CD40 ligand, IL-4, CpG oligonucleotides, lysophosphatidic acid, high-density lipoprotein particles and contact with bone marrow stromal cells. [6][7][8][9][10][11][12][13] In addition, increased basal Akt activity has been reported in some studies, suggesting that constitutive Akt signaling may contribute to the increased survival of the malignant lymphocytes. In line with this possibility, specific inhibition or downregulation of Akt has been shown to induce apoptosis in freshly isolated CLL cells.…”

Section: Introductionmentioning

confidence: 97%

Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells

et al. 2010

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The PI3K/Akt pathway is activated in response to various microenvironmental stimuli that regulate the survival and proliferation of chronic lymphocytic leukemia (CLL) B-cells, including triggering of the B-cell receptor (BCR). Although this pathway is frequently targeted in cancer, no significant alterations have yet been identified in CLL. We now show that the phosphatase PH domain leucin-rich repeat protein phosphatase (PHLPP1), a recently identified tumor suppressor and negative regulator of the Akt kinase, is absent or expressed at substantially reduced levels in CLL B-cells. To determine what the consequences of PHLPP1 loss on BCR signaling are, we downregulated or re-expressed PHLPP1 in lymphoma cell lines and primary CLL B-cells, respectively. Downregulation of PHLPP1 increased BCR-induced phosphorylation and activation of the Akt, GSK3 and ERK kinases, whereas re-expression had the opposite effect. Importantly, re-expression of PHLPP1 in primary CLL cells prevented upregulation of Mcl-1 and inhibited the increase in leukemic cell viability induced by sustained BCR engagement. Enforced expression of PHLPP1 also affected the response to other microenvironmental stimuli, particularly in terms of ERK phosphorylation. Collectively, these data show that CLL cells lack an important negative regulator of the Akt and ERK pathways, which could confer them a growth advantage by facilitating the propagation of crucial microenvironment-derived stimuli.

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Chronic lymphocytic leukemia (CLL)—Then and now

Kanti

Jain²

2016

American J Hematol

134

108

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The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO-1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo-immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kd inhibitor) and novel anti-CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT-199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. It is a disease of progressive accumulation of lymphocytes. CLL lymphocytes are morphologically indistinguishable from a normal mature lymphocyte CLL lymphocytes are functionally inert and perhaps as a direct consequence, their life-span is longer than of normal lymphocytes. It was also believed that CLL lymphocytes are not rapidly proliferating. CLL is a disease of elderly population In some cases, chronic lymphocytic leukemia (CLL) closely resembled leukemic Brill Symmers disease (leukemic form of follicular lymphoma). In an elegant study on 88 patients, the temporal profile of the clinical course of CLL was described by Galton et al.[1] Disease progression was assessed in relation to lymphadenopathy, splenomegaly and bone marrow infiltration. CLL was considered as an immunoproliferative disorder with low immunoglobulin levels, striking response to therapy with steroids and exaggerated skin reaction to arthropod bites. Management of CLL (then in 1976)Most clinicians recognized that at the time of initial diagnosis, patients with CLL, generally, were free of disease-related symptoms. Therefore, virtually all patients were followed on a wait-and-watch regimen, withholding any cytotoxic therapy. When, on clinical grounds, initiation of any therapy was considered appropriate, oral alkylating agents such as chlorambucil with/without steroids [3,4] or cyclophosphamide [5] with or...

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The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease

Cited by 135 publications

References 60 publications

Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells

Chronic lymphocytic leukemia (CLL)—Then and now

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