Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3807-3817 ◽  
Author(s):  
Chris Pepper ◽  
Thet Thet Lin ◽  
Guy Pratt ◽  
Saman Hewamana ◽  
Paul Brennan ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Mutation ◽  
Prognostic Markers ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Vh Gene

Bcl-2 family proteins play a critical role in the regulation of apoptosis in chronic lymphocytic leukemia (CLL). However, their association with established prognostic markers is unknown. In this study, we analyzed the expression of Bcl-2, Bax, and Mcl-1 in 185 CLL patients and evaluated their relationship with other prognostic markers, in vitro sensitivity to fludarabine, and clinical outcome. Mcl-1 expression was significantly correlated with stage of disease (P < .001), lymphocyte doubling time (P = .01), VH gene mutation status (P < .001), CD38 expression (P < .001), and ZAP-70 expression (P = .003). In addition, Mcl-1 and Mcl-1/Bax ratios showed strong correlations with in vitro resistance to fludarabine (P = .005 and P < .001, respectively). Furthermore, elevated Mcl-1 expression and Mcl-1/Bax ratios were predictive of time to first treatment in the whole cohort (P < .001 and P < .001, respectively) and in stage A patients only (P = .002 and P = .001, respectively). Taken together, our data show that Mcl-1 is a key controller of in vitro drug resistance and is an important regulator of disease progression and outcome in CLL. It therefore represents a promising therapeutic target in this incurable condition. The close correlation between Mcl-1 expression and VH gene mutation status, CD38 expression, and ZAP-70 expression offers a biologic explanation for their association with adverse prognosis.

Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4807-4812 ◽  
Author(s):  
Pawel Grabowski ◽  
Magnus Hultdin ◽  
Karin Karlsson ◽  
Gerard Tobin ◽  
Anna Åleskog ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Telomere Length ◽  
Gene Mutation ◽  
Quantitative Polymerase Chain Reaction ◽  
Lymphocytic Leukemia ◽  
Prognostic Information ◽  
Mutation Status ◽  
Patient Groups ◽  
Vh Gene ◽  
Polymerase Chain

Abstract B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin VH genes have better outcome than unmutated cases. VH-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, VH gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P &lt; .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P &lt; .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P &lt; .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the VH-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining VH mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes. (Blood. 2005;105:4807-4812)

Ig V Gene Mutation Status and CD38 Expression As Novel Prognostic Indicators in Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1840-1847 ◽  
Author(s):  
Rajendra N. Damle ◽  
Tarun Wasil ◽  
Franco Fais ◽  
Fabio Ghiotto ◽  
Angelo Valetto ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Mutation ◽  
Lymphocytic Leukemia ◽  
Prognostic Indicators ◽  
Risk Category ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Staging Systems ◽  
V Genes ◽  
V Gene

Abstract Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM+ B-chronic lymphocytic leukemia (B-CLL) cases for which Ig VH and VL gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38+ B-CLL cells (≥30%) than those with mutated V genes that had lower percentages of CD38+ cells (&lt;30%). Patients in both the unmutated and the ≥30% CD38+ groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the &lt;30% CD38+ groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the &lt;30% CD38+ groups, males and females were virtually equally distributed, whereas in the unmutated and the ≥30% CD38+ groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38+B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.

scholarly journals RhoH is critical for cell-microenvironment interactions in chronic lymphocytic leukemia in mice and humans

Blood ◽  
2012 ◽  
Vol 119 (20) ◽  
pp. 4708-4718 ◽  
Author(s):  
Anja Troeger ◽  
Amy J. Johnson ◽  
Jenna Wood ◽  
William G. Blum ◽  
Leslie A. Andritsos ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Critical Role ◽  
Disease Onset ◽  
Lymphocytic Leukemia ◽  
Cell Contact ◽  
Cell Microenvironment ◽  
The Impact ◽  
Cell Cell

Abstract Trafficking of B-cell chronic lymphocytic leukemia (CLL) cells to the bone marrow and interaction with supporting stromal cells mediates important survival and proliferation signals. Previous studies have demonstrated that deletion of Rhoh led to a delayed disease onset in a murine model of CLL. Here we assessed the impact of RhoH on homing, migration, and cell-contact dependent interactions of CLL cells. Rhoh−/− CLL cells exhibited reduced marrow homing and subsequent engraftment. In vitro migration toward the chemokines CXCL12 and CXCL13 and cell-cell interactions between Rhoh−/− CLL cells and the supporting microenvironment was reduced. In the absence of RhoH the distribution of phosphorylated focal adhesion kinase, a protein known to coordinate activation of the Rho GTPases RhoA and Rac, appeared less polarized in chemokine-stimulated Rhoh−/− CLL cells, and activation and localization of RhoA and Rac was dysregulated leading to defective integrin function. These findings in the Rhoh−/− CLL cells were subsequently demonstrated to closely resemble changes in GTPase activation observed in human CLL samples after in vitro and in vivo treatment with lenalidomide, an agent with known influence on microenvironment protection, and suggest that RhoH plays a critical role in prosurvival CLL cell-cell and cell-microenvironment interactions with this agent.

CD38 expression and Ig VH gene mutation in B-cell chronic lymphocytic leukemia

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1902-1902 ◽  
Author(s):  
Zoltan Matrai ◽  
Ke Lin ◽  
Michael Dennis ◽  
Paul Sherrington ◽  
Mirko Zuzel ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Gene Mutation ◽  
Lymphocytic Leukemia ◽  
Cd38 Expression ◽  
Vh Gene ◽  
Cell Chronic Lymphocytic Leukemia

Integrating Prognostic Markers and Cellular Signaling Identifies More Chronic Lymphocytic Leukemia Patients with Adverse Prognosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2782-2782
Author(s):  
Paul Brennan ◽  
Suhair Alghazal ◽  
Naomi Price Lloyd ◽  
Janet E. Williams ◽  
Jeff D. Griffiths ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Phosphorylation ◽  
Gene Mutation ◽  
Lymphocytic Leukemia ◽  
Training Dataset ◽  
Mutation Status ◽  
Patients At Risk ◽  
Vh Gene ◽  
Cell Signal Transduction ◽  
Time To First Treatment

Abstract In this study we devised an equation that provides a new way of identifying B-cell chronic lymphocytic leukemia (CLL) patients who will require early therapeutic intervention. The equation was developed by studying the biology of the disease with a focus on cell signal transduction. Using statistical analysis, we show that measured tyrosine phosphorylation can be described as a function of VH gene mutation status, and the expression of ZAP-70 and CD38 (r2 = 0.81, n = 49). Furthermore, we show that tyrosine phosphorylation has biological relevance as it sets a threshold for the activation of the transcription factor, NF-kB, resulting in the modulation of cell survival. Using the equation derived from our training dataset we calculated tyrosine phosphorylation in a cohort of 155 unselected CLL patient samples. The patient cohort was then divided into those with calculated tyrosine phosphorylation above or below the threshold required to activate NF-kB. Patients with high calculated tyrosine phosphorylation had a shorter time to first treatment. This method identified more patients at risk of requiring early treatment than VH gene mutation status, ZAP-70 or CD38. Furthermore, calculated tyrosine phosphorylation identifies patients that will require early intervention within the mutated VH gene cohort and even patients that have Stage A disease.

Ig V Gene Mutation Status and CD38 Expression As Novel Prognostic Indicators in Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1840-1847 ◽  
Author(s):  
Rajendra N. Damle ◽  
Tarun Wasil ◽  
Franco Fais ◽  
Fabio Ghiotto ◽  
Angelo Valetto ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Mutation ◽  
Lymphocytic Leukemia ◽  
Prognostic Indicators ◽  
Risk Category ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Staging Systems ◽  
V Genes ◽  
V Gene

Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM+ B-chronic lymphocytic leukemia (B-CLL) cases for which Ig VH and VL gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38+ B-CLL cells (≥30%) than those with mutated V genes that had lower percentages of CD38+ cells (<30%). Patients in both the unmutated and the ≥30% CD38+ groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the <30% CD38+ groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the <30% CD38+ groups, males and females were virtually equally distributed, whereas in the unmutated and the ≥30% CD38+ groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38+B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.

Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 1087-1093 ◽  
Author(s):  
Stuart Lanham ◽  
Terry Hamblin ◽  
David Oscier ◽  
Rachel Ibbotson ◽  
Freda Stevenson ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Course ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cd38 Expression ◽  
Mutational Status ◽  
Vh Gene ◽  
Vh Genes ◽  
Gene Status

Abstract The mutational status of tumor immunoglobulin VHgenes is providing a powerful prognostic marker for chronic lymphocytic leukemia (CLL), with patients having tumors expressing unmutated VH genes being in a less favorable subset. However, the biologic differences correlating with VH gene status that could determine the clinical course of the disease are unknown. Here we show that differing responses to IgM ligation are closely associated with VH gene status. Specifically, 80% of cases with unmutated VH genes showed increased global tyrosine phosphorylation following IgM ligation, whereas only 20% of samples with mutated VH genes responded (P = .0002). There was also an association between response to IgM ligation and expression of CD38 (P = .015). The Syk kinase, critical for transducing B-cell receptor (BCR)– derived signals, was constitutively present in all CLL samples, and there was a perfect association between global phosphorylation and induction of phosphorylation/activation of Syk. Nonresponsiveness to anti-IgM could be circumvented by ligation of IgD (10 of 15 samples tested) or the BCR-associated molecule CD79α (12 of 15 samples tested). These results suggest that multiple mechanisms underlie nonresponsiveness to anti-IgM in CLL and that retained responsiveness to anti-IgM contributes to the poor prognosis associated with the unmutated subset of CLL. The prognostic power of the in vitro response to IgM ligation remains to be determined in a large series, but the simple technology involved may present an alternative or additional test for predicting clinical course.

Evaluation of vecabrutinib as a model for non-covalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia

Blood ◽  
2021 ◽  
Author(s):  
Billy Michael Chelliah Jebaraj ◽  
Annika Müller ◽  
Rashmi Priyadharshini Dheenadayalan ◽  
Sascha Endres ◽  
Philipp M. Roessner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Inhibitory Effect ◽  
Lymphocytic Leukemia ◽  
Transfer Model ◽  
Treatment Benefit ◽  
Btk Inhibitors

Covalent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop by a mutation in cysteine 481 of BTK (C481S), which prevents the irreversible binding of the drugs. In the present study we performed pre-clinical characterization of vecabrutinib, a next generation non-covalent BTK inhibitor, with ITK inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wildtype BTK. In the murine Eµ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+ effector and memory T-cell populations, while the naïve populations were increased. Of importance, vecabrutinib treatment significantly reduced frequency of regulatory CD4+ T-cells (Tregs) in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on activation and proliferation of isolated T-cells. Lastly, combination treatment of vecabrutinib with venetoclax was found to augment treatment efficacy, significantly improve survival and lead to favourable reprogramming of the microenvironment in the murine Eµ-TCL1 model. Thus, non-covalent BTK/ITK inhibitors such as vecabrutinib may be efficacious in C481S BTK mutant CLL, while preserving the T-cell immunomodulatory function of ibrutinib.

Chronic lymphocytic leukemia: revelations from the B-cell receptor

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4389-4395 ◽  
Author(s):  
Freda K. Stevenson ◽  
Federico Caligaris-Cappio
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Regulatory B Cell ◽  
V Genes

Abstract The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. (Blood. 2004;103:4389-4395)

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