c-Abl Expression in Chronic Lymphocytic Leukemia Cells: Clinical and Therapeutic Implications

Lin, Ke; Glenn, Mark A.; Harris, Robert J.; Duckworth, Andrew D.; Dennett, Sally; Cawley, James F.; Zuzel, Mirko; Slupsky, Joseph R.

doi:10.1158/0008-5472.can-05-3901

Cited by 33 publications

(42 citation statements)

References 45 publications

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“…All CLL cell samples used for this study had been cryopreserved and stored within the Liverpool Leukaemia Biobank. When required, cells were thawed, resuspended in culture media, and equilibrated as described previously (28). All cases used in this study were chosen at random and had a minimum viability of 80%.…”

Section: Patient Samplesmentioning

confidence: 99%

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

Talab

Allen

Thompson

et al. 2013

Molecular Cancer Research

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B-cell receptor (BCR) signals promote survival of chronic lymphocytic leukemia (CLL) cells, and it is believed that overexpressed and constitutively active Lyn mediates this signaling. Here, we show that CLL cells express lymphocyte-specific protein tyrosine kinase (LCK) and that inhibition of this Src family tyrosine kinase with the specific inhibitor [4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[3,2-d]pyrimidin-7-yl-cyclopentane (Lck-i)], or reduction of its expression with siRNA, blocks the induction of CD79a, Syk, inhibitor of IkB kinase (IKK), Akt, and extracellular signal-regulated kinase (ERK) phosphorylation by BCR cross-linking in these cells. Furthermore, we show that CLL cells with high levels of LCK expression have higher levels of BCR-mediated IKK, Akt, and ERK phosphorylation as well as cell survival than CLL cells with low levels of LCK expression. We also show that treatment of CLL cells with Lck-i inhibits BCR cross-linking-induced cell survival. Taken together, these data show a major role for LCK in proximal and distal BCR-mediated signaling in CLL cells and suggest that LCK expression is important in the pathogenesis of this disease. On a clinical level, these studies advocate the use of specific LCK inhibitors in the treatment of progressive CLL. Mol Cancer Res; 11(5); 541-54. Ó2013 AACR.

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Section: Patient Samplesmentioning

confidence: 99%

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

Talab

Allen

Thompson

et al. 2013

Molecular Cancer Research

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“…Cryopreserved CLL cells from the University of Liverpool Leukemia Tissue Bank were thawed and used as previously described. 29 For CLL samples which comprised ,95% malignant (CD5 1 CD19 1 ) cells and for all normal B preparations, cells were purified (to .95% CD5 1 CD19 1 cells) using negative selection (MACS system; Miltenyi Biotec). Cells were cultured at 37°C with a density of 3 3 10 6 cells/mL in culture media (RPMI-1640 [Sigma-Aldrich] supplemented with 0.5% [w/v] bovine serum albumin, 2 mM L-glutamine, 100 units/mL penicillin, and 100 mg/mL streptomycin).…”

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confidence: 99%

Variable induction of PRDM1 and differentiation in chronic lymphocytic leukemia is associated with anergy

Duckworth

Glenn

Slupsky

et al. 2014

Blood

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Key Points• Differentiation of CLL cells in response to IL-21 and cytosine guanine dinucleotide-enriched oligo-deoxynucleotides (CpG-ODN) is variable and linked to PRDM1 induction.• The failure of CLL cells to express or induce PRDM1 correlates with anergy.Despite antigen engagement and intact B-cell-receptor (BCR) signaling, chronic lymphocytic leukemia (CLL) cells fail to undergo terminal differentiation. We hypothesized that such failure may be due to anergy, as CLL cells exhibit variable levels of nonresponsiveness to surface IgM stimulation that is reversible in vitro. Moreover, anergy is associated with reduced differentiation capacity in normal B cells. We investigated responses of CLL cells to two potent differentiation-promoting agents, IL-21 and cytosine guanine dinucleotide-enriched oligo-deoxynucleotides. The induction of PR domaincontaining protein 1 (PRDM1; also known as Blimp-1), a critical regulator of plasmacytic differentiation, by these agents was closely correlated but varied between individual cases, despite functionally intact IL-21 receptor-and Toll-like receptor 9-mediated signal transducer and activator of transcription 3, and nuclear factor-kB pathways. PRDM1 induction was inversely correlated with the extent of anergy as measured by the ability to mobilize intracellular Ca 21 following BCR crosslinking. PRDM1 responsiveness was associated with other markers of differentiation and proliferation but not with differences in apoptosis. The ability to induce PRDM1 did correlate with differential transcriptional and epigenetic regulation of the PRDM1 gene. These studies extend our understanding of CLL pathobiology, demonstrating that reduced differentiation capacity may be a consequence of anergy. Epigenetic drugs may offer possibilities to reactivate PRDM1 expression as part of novel differentiation therapy approaches. (Blood. 2014;123(21):3277-3285) IntroductionChronic lymphocytic leukemia (CLL) is a malignancy of B lymphocytes that retain dependency on extracellular stimuli for their survival and behavior. Two major CLL subsets have been identified which arise at distinct stages of B-cell differentiation and are characterized by varying levels of somatic hypermutation of immunoglobulin (Ig) V-genes.1 Importantly, these subsets exhibit very different clinical behavior. CLL with unmutated V-genes (U-CLL) appears to develop from naive B cells of the natural antibody repertoire with specificity for common pathogens and has a significantly worse prognosis compared with CLL with mutated V-genes (M-CLL). [2][3][4][5] Further support for a role of antigen stimulation in CLL is provided by the presence of biased V-gene usage in both subsets and the presence of conserved sequence motifs within the complementarity determining region 3s of CLL-derived B-cell receptors (BCRs).6-8 Putative CLL antigens have been identified, including self-antigens, or antigens derived from common pathogens including viruses, bacteria, and fungi. 9 The idea that BCR signaling is important in CLL is supported by rece...

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“…43 The ability to inhibit ABL was exploited in a recent clinical trial of Philadelphia chromosome-positive chronic myeloid and acute lymphocytic leukemia, which haematologica | 2012; 97(8) 44 The ABL kinase may also represent a therapeutic target in CLL, as this kinase is highly expressed and constitutively active in CLL cells. 45 Moreover, inhibition or downregulation of Abl has been reported to reduce the expression of the anti-apoptotic protein Mcl-1 and induce leukemic cell apoptosis. [45][46] Although we did not observe a direct cytotoxic effect of VX-680 against resting CLL cells, it remains possible that this compound could enhance the sensitivity of these cells to other cytotoxic agents by down-regulating Mcl-1.…”

confidence: 99%

“…45 Moreover, inhibition or downregulation of Abl has been reported to reduce the expression of the anti-apoptotic protein Mcl-1 and induce leukemic cell apoptosis. [45][46] Although we did not observe a direct cytotoxic effect of VX-680 against resting CLL cells, it remains possible that this compound could enhance the sensitivity of these cells to other cytotoxic agents by down-regulating Mcl-1.…”

confidence: 99%

The Aurora A and B kinases are up-regulated in bone marrow-derived chronic lymphocytic leukemia cells and represent potential therapeutic targets

Careta¹,

Gobessi²,

Panepucci³

et al. 2012

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundThe malignant B cells in chronic lymphocytic leukemia receive signals from the bone marrow and lymph node microenvironments which regulate their survival and proliferation. Characterization of these signals and the pathways that propagate them to the interior of the cell is important for the identification of novel potential targets for therapeutic intervention. Design and MethodsWe compared the gene expression profiles of chronic lymphocytic leukemia B cells purified from bone marrow and peripheral blood to identify genes that are induced by the bone marrow microenvironment. Two of the differentially expressed genes were further studied in cell culture experiments and in an animal model to determine whether they could represent appropriate therapeutic targets in chronic lymphocytic leukemia. ResultsFunctional classification analysis revealed that the majority of differentially expressed genes belong to gene ontology categories related to cell cycle and mitosis. Significantly up-regulated genes in bone marrow-derived tumor cells included important cell cycle regulators, such as Aurora A and B, survivin and CDK6. Down-regulation of Aurora A and B by RNA interference inhibited proliferation of chronic lymphocytic leukemia-derived cell lines and induced low levels of apoptosis. A similar effect was observed with the Aurora kinase inhibitor VX-680 in primary chronic lymphocytic leukemia cells that were induced to proliferate by CpG-oligonucleotides and interleukin-2. Moreover, VX-680 significantly blocked leukemia growth in a mouse model of chronic lymphocytic leukemia. ConclusionsAurora A and B are up-regulated in proliferating chronic lymphocytic leukemia cells and represent potential therapeutic targets in this disease.Key words: chronic lymphocytic leukemia, microenvironment, Aurora kinase, novel therapeutic targets. Haematologica 2012;97(8):1246-1254. doi:10.3324/haematol.2011 This is an open-access paper. Citation: de Paula Careta F, Gobessi S, Panepucci RA, Bojnik E, Morato de Oliveira F, Mazza Matos D, Falcão RP, Laurenti L, Zago MA, and Efremov DG. The Aurora A and B kinases are up-regulated in bone marrow-derived chronic lymphocytic leukemia cells and represent potential therapeutic targets.The Aurora A and B kinases are up-regulated in bone marrow-derived chronic lymphocytic leukemia cells and represent potential therapeutic targets ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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c-Abl Expression in Chronic Lymphocytic Leukemia Cells: Clinical and Therapeutic Implications

Cited by 33 publications

References 45 publications

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

Variable induction of PRDM1 and differentiation in chronic lymphocytic leukemia is associated with anergy

The Aurora A and B kinases are up-regulated in bone marrow-derived chronic lymphocytic leukemia cells and represent potential therapeutic targets

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