The Novel Histone Deacetylase Inhibitor OSU-HDAC42 Has Class I and II Histone Deacetylase (HDAC) Inhibitory Activity and Represents a Novel Therapy for Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2807-2807
Author(s):  
Derek A. West ◽  
David M. Lucas ◽  
Melanie E. Davis ◽  
Michael D. De Lay ◽  
Amy J. Johnson ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Histone Deacetylase ◽  
Inhibitory Activity ◽  
Hdac Inhibitors ◽  
Clinical Development ◽  
Lymphocytic Leukemia ◽  
In Vivo Efficacy

Abstract Inhibitors of histone deacetylase (HDAC) have generated major interest for the treatment of multiple cancers including B-cell Chronic Lymphocytic Leukemia (CLL). To date, HDAC inhibitors introduced for clinical development in CLL have been associated either with suboptimal activity relative to concentrations required to mediate cytotoxicity in vitro (Valproic Acid, MS-275, SAHA), or demonstrate unacceptable acute or long-term toxicities (depsipeptide) that limit their clinical potential. Fortunately, several alternative HDAC inhibitors are in pre-clinical or early clinical development. One such agent currently undergoing pre-clinical testing by the National Cancer Institute-sponsored RAID program is OSU-HDAC42 (s-HDAC-42), a novel, orally bioavailable phenylbutyrate-derived HDAC inhibitor with both in vitro and in vivo efficacy against prostate cancer cells. We therefore tested OSU-HDAC42 against CD19-positive cells obtained from patients with CLL to determine its potential in this disease. The LC50 of OSU-HDAC42 in CLL cells was 0.46 uM at 48 hours of continuous incubation by MTT assay, which was corroborated by annexin V-FITC/propidium iodide flow cytometry. To determine the minimum amount of time that OSU-HDAC42 must be present to induce cell death, cells were incubated for various times, washed, resuspended in fresh media without drug, then assessed by MTT at a total of 48 hours incubation. The effects of OSU-HDAC42 were eliminated in CLL cells when drug was removed after 4 or 6 hours. However, there was a gradual increase in effect over time, and by 16 hours, approximately 60% of the cytotoxicity achieved with continuous incubation was retained. OSU-HDAC42 induced acetylation of histone proteins H3 and H4 as early as 4 hours that was dose and time dependent. LC/MS interrogation of OSU-HDAC42-treated CLL cells is currently underway to determine specific post-translational modification changes of all histone proteins and variants. OSU-HDAC42 also was able to sensitize CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL) at 24 hours in a dose-dependent manner, supporting its class I HDAC inhibitory activity as recently reported by Inoue and colleagues (Cancer Res.2006; 66:6785). Evidence of class II HDAC inhibitory activity was also observed with OSU-HDAC42 at 12 hours with acetylation of tubulin. Unlike depsipeptide, OSU-HDAC42 activated both caspase-8 and -9 followed by PARP processing. Cell death induced by OSU-HDAC42 was completely inhibited with pre-treatment by the pan-caspase inhibitor Z-VAD-FMK. In vivo experiments are underway to examine the efficacy of OSU-HDAC42 in several murine models of leukemia to confirm in vivo efficacy as well as influence on murine effector cells. Our data strongly support continued investigation of OSU-HDAC42 in CLL and related B-cell malignancies.

In Vitro Activity of a Novel Fully Human Anti-CD40 Antibody CHIR-12.12 in Chronic Lymphocytic Leukemia: Blockade of CD40 Activation and Induction of ADCC.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2504-2504 ◽  
Author(s):  
Xia Tong ◽  
Georgios V. Georgakis ◽  
Long Li ◽  
O’Brien Susan ◽  
Younes Anas ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Line ◽  
Blood Donors ◽  
Lymphocytic Leukemia ◽  
Dependent Manner ◽  
Dose Dependent

Abstract B-cell chronic lymphocytic leukemia (CLL) is characterized by in vivo accumulation of long-lived CD5+ B cells. However when cultured in vitro CLL cells die quickly by apoptosis. Protection from apoptosis in vivo is believed to result from supply of survival signals provided by cells in the microenvironment. We and others have previously reported that CLL cells express CD40 receptor, and that CD40 stimulation of CLL cells may rescue CLL cells from spontaneous and drug-induced apoptosis in vitro. These observations suggested that blocking CD40-CD40L pathway might deprive CLL cells from survival signals and induce apoptosis. To test this hypothesis, we have generated a fully human anti-CD40 blocking monoclonal antibody in XenoMousemice (Abgenix, Inc.). The antibody CHIR-12.12 was first evaluated for its effect on normal human lymphocytes. Lymphocytes from all 10 healthy blood donors did not proliferate in response to CHIR-12.12 at any concentration tested (0.0001 mg/ml to 10 mg/ml range). In contrast, activating CD40 on normal B-lymphocytes by CD40L induced their proliferation in vitro. Importantly, CHIR-12.12 inhibited CD40L- induced proliferation in a dose dependent manner with an average IC50 of 51 ± 26 pM (n=10 blood donors). The antagonistic activity of CHIR-12.12 was then tested in primary CLL samples from 9 patients. CHIR-12.12 alone did not induce CLL cell proliferation. In contrast, primary CLL cells incubated with CD40L, either resisted spontaneous cell death or proliferated. This effect was reversed by co-incubation with CHIR-12.12 antibody, restoring CLL cell death (n=9). CHIR-12.12 was then examined for its ability to lyse CLL cell line EHEB by antibody dependent cell mediated cytotoxicity (ADCC). Freshly isolated human NK cells from normal volunteer blood donors were used as effector cells. CHIR-12.12 showed lysis activity in a dose dependent manner and produced maximum lysis levels at 0.1 mg/ml. When compared with rituximab, CHIR-12.12 mediated greater maximum specific lysis (27.2 % Vs 16.2 %, p= 0.007). The greater ADCC by CHIR-12.12 was not due to higher density of CD40 molecules on CLL cell line compared to CD20 molecules. The CLL target cells expressed 509053 ±13560 CD20 molecules compared to 48416 ± 584 CD40 molecules. Collectively, these preclinical data suggest that CHIR-12.12 monoclonal antibody may have a therapeutic role in patients with CLL.

The Valproic Acid-Fludarabine Combination Induces a Synergistic Response in Chronic Lymphocytic Leukemia Via a Mechanism Involving the Lysosomal Protease Cathepsin B.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2892-2892
Author(s):  
Ju-Yoon Yoon ◽  
David Szwajcer ◽  
Ganchimeg Ishdorj ◽  
Pat Benjaminson ◽  
James B Johnston ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Cathepsin B ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Lysosomal Protease

Abstract Abstract 2892 Chronic Lymphocytic Leukemia (CLL) is the most common haematological malignancy in the western world. Fludarabine, a nucleoside analogue, is commonly used to treat Chronic Lymphocytic Leukemia (CLL) in untreated and relapsed CLL. However, patients commonly develop resistance to fludarabine. We hypothesize that the addition of Valproic Acid (VPA), an inhibitor of histone deacetylases (HDACs), can improve fludarabine-based therapy. The VPA-Fludarabine combination induced a synergistic response in human leukemic cells and primary CLL cells. Fludarabine also interacted synergistically with three other HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), Trichostatin A, and sodium butyrate, while the synergy was not observed with valpromide, the VPA analogue that does not inhibit HDACs. We confirmed that fludarabine treatment activates caspases-8, -9 and caspase-3, and we also show that fludarabine treatment activates caspase-2, an upstream caspase that has been implicated in cell death associated with lysosome membrane permeabilization (LMP). Activation of all four caspases was enhanced by the addition of VPA. Enhanced activation of caspases was associated with down-regulation of two prominent anti-apoptotic proteins, Mcl-1 and XIAP. The down-regulation of Mcl-1 and XIAP was dependent on the lysosomes, as their alkalinization using either chloroquine or NH4Cl partially stabilized both proteins, leading to reduced apoptosis. Chemical inhibition of a specific lysosomal protease, cathepsin B, using CA074-Me, was sufficient to stabilize Mcl-1 and XIAP, reduce caspase activation and apoptosis. Treatment with fludarabine or the VPA-fludarabine combination led to the loss of lysosome integrity, as visualized by fluorescent staining, thus suggesting a leakage of the lysosomal content into the cytosol in response to the drugs. Addition of purified cathepsin B to leukemic cell lysates led to the reduction in protein levels of Mcl-1, XIAP and pro-caspase-2, thus suggesting that the re-localization of cathepsin B into the cytosol is sufficient to drive cell death. VPA treatment enhanced cathepsin B levels in both leukemic cell lines and primary CLL cells. When cathepsin B activity was examined using zRR-AMC, a fluorogenic substrate of cathepsin B, VPA also increased cathepsin B activity, and this activity was abolished by the addition of CA074-Me. In parallel with the in vitro/ex vivo experiments, we had launched a phase II clinical trial at CancerCare Manitoba. Six relapsed CLL patients who had received at least one prior therapy with fludarabine were examined. No responses were seen after 28 days using VPA alone, in line with the in vitro observation of minimal cytotoxicity of VPA at low doses. However, in five patients who continued on VPA with fludarabine, three patients showed a >50% fall in lymphocyte/lymph node size after receiving five cycles of the combination. When the leukemic cells from VPA-treated CLL patients were examined, VPA administration induced increased levels of histone-3 acetylation and cathepsin B in vivo. In summary, a novel mechanism for fludarabine cytotoxicity has been elucidated, where fludarabine induces a loss of lysosomal integrity, leading to cathepsin B-dependent cell death. VPA interacted with fludarabine synergistically, and this synergy was associated with the VPA-induced increase in VPA level and activity. VPA induced increase in histone-3 acetylation and cathepsin B in vivo, and this induction of cathepsin B is likely to be contributing to the clinical response observed in fludarabine-relapsed/refractory CLL patients. Disclosures: Off Label Use: Valproic acid as adjunct therapy in Chronic Lymphocytic Leukemia. Johnston:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Expression of Apoptosis-Regulating Proteins in Chronic Lymphocytic Leukemia: Correlations With In Vitro and In Vivo Chemoresponses

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3379-3389 ◽  
Author(s):  
Shinichi Kitada ◽  
Janet Andersen ◽  
Sophie Akar ◽  
Juan M. Zapata ◽  
Shinichi Takayama ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Caspase 3 ◽  
Single Agent ◽  
White Blood Cells ◽  
Lymphocytic Leukemia ◽  
In Vitro Chemosensitivity ◽  
Apoptotic Protein

Abstract B-cell chronic lymphocytic leukemia (B-CLL) represents a neoplastic disorder caused primarily by defective programmed cell death (PCD), as opposed to increased cell proliferation. Defects in the PCD pathway also contribute to chemoresistance. The expression of several apoptosis-regulating proteins, including the Bcl-2 family proteins Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, and BAD; the Bcl-2–binding protein BAG-1; and the cell death protease Caspase-3 (CPP32), was evaluated by immunoblotting using 58 peripheral blood B-CLL specimens from previously untreated patients. Expression of Bcl-2, Mcl-1, BAG-1, Bax, Bak, and Caspase-3 was commonly found in circulating B-CLL cells, whereas the Bcl-XL and BAD proteins were not present. Higher levels of the anti-apoptotic protein Mcl-1 were strongly correlated with failure to achieve complete remission (CR) after single-agent therapy (fludarabine or chlorambucil) (P = .001), but the presence of only seven CRs among the 42 patients for whom follow-up data were available necessitates cautious interpretation of these observations. Higher levels of the anti-apoptotic protein BAG-1 were also marginally associated with failure to achieve CR (P = .04). Apoptosis-regulating proteins were not associated with patient age, sex, Rai stage, platelet count, hemoglobin (Hb) concentration, or lymph node involvement, although higher levels of Bcl-2 and a high Bcl-2:Bax ratio were correlated with high numbers (>105/μL) of white blood cells (WBC) (P = .01; .007) and higher levels of Bak were weakly associated with loss of allelic heterozygosity at 13q14 (P = .04). On the basis of measurements of apoptosis induction by fludarabine using cultured B-CLL specimens, in vitro chemosensitivity data failed to correlate with in vivo clinical response rates (n = 42) and expression of the various apoptosis-regulating proteins. Although larger prospective studies are required before firm conclusions can be reached, these studies show the expression in B-CLLs of multiple apoptosis-regulating proteins and suggest that the relative levels of some of these, such as Mcl-1, may provide information about in vivo responses to chemotherapy. In vitro chemosensitivity data, however, do not appear to be particularly useful in predicting responses in B-CLL.

scholarly journals Expression of Apoptosis-Regulating Proteins in Chronic Lymphocytic Leukemia: Correlations With In Vitro and In Vivo Chemoresponses

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3379-3389 ◽  
Author(s):  
Shinichi Kitada ◽  
Janet Andersen ◽  
Sophie Akar ◽  
Juan M. Zapata ◽  
Shinichi Takayama ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Caspase 3 ◽  
Single Agent ◽  
White Blood Cells ◽  
Lymphocytic Leukemia ◽  
In Vitro Chemosensitivity ◽  
Apoptotic Protein

B-cell chronic lymphocytic leukemia (B-CLL) represents a neoplastic disorder caused primarily by defective programmed cell death (PCD), as opposed to increased cell proliferation. Defects in the PCD pathway also contribute to chemoresistance. The expression of several apoptosis-regulating proteins, including the Bcl-2 family proteins Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, and BAD; the Bcl-2–binding protein BAG-1; and the cell death protease Caspase-3 (CPP32), was evaluated by immunoblotting using 58 peripheral blood B-CLL specimens from previously untreated patients. Expression of Bcl-2, Mcl-1, BAG-1, Bax, Bak, and Caspase-3 was commonly found in circulating B-CLL cells, whereas the Bcl-XL and BAD proteins were not present. Higher levels of the anti-apoptotic protein Mcl-1 were strongly correlated with failure to achieve complete remission (CR) after single-agent therapy (fludarabine or chlorambucil) (P = .001), but the presence of only seven CRs among the 42 patients for whom follow-up data were available necessitates cautious interpretation of these observations. Higher levels of the anti-apoptotic protein BAG-1 were also marginally associated with failure to achieve CR (P = .04). Apoptosis-regulating proteins were not associated with patient age, sex, Rai stage, platelet count, hemoglobin (Hb) concentration, or lymph node involvement, although higher levels of Bcl-2 and a high Bcl-2:Bax ratio were correlated with high numbers (>105/μL) of white blood cells (WBC) (P = .01; .007) and higher levels of Bak were weakly associated with loss of allelic heterozygosity at 13q14 (P = .04). On the basis of measurements of apoptosis induction by fludarabine using cultured B-CLL specimens, in vitro chemosensitivity data failed to correlate with in vivo clinical response rates (n = 42) and expression of the various apoptosis-regulating proteins. Although larger prospective studies are required before firm conclusions can be reached, these studies show the expression in B-CLLs of multiple apoptosis-regulating proteins and suggest that the relative levels of some of these, such as Mcl-1, may provide information about in vivo responses to chemotherapy. In vitro chemosensitivity data, however, do not appear to be particularly useful in predicting responses in B-CLL.

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)

scholarly journals ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells

Blood ◽  
2016 ◽  
Vol 127 (5) ◽  
pp. 582-595 ◽  
Author(s):  
Marwan Kwok ◽  
Nicholas Davies ◽  
Angelo Agathanggelou ◽  
Edward Smith ◽  
Ceri Oldreive ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Synthetic Lethality ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Selective Cytotoxicity ◽  
Key Points ◽  
Synthetically Lethal

Key PointsATR inhibition is synthetically lethal to TP53- or ATM-defective CLL cells. ATR targeting induces selective cytotoxicity and chemosensitization in TP53- or ATM-defective CLL cells in vitro and in vivo.

Nurture versus Nature: The Microenvironment in Chronic Lymphocytic Leukemia

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 96-103 ◽  
Author(s):  
Jan A. Burger
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Disease Progression ◽  
Drug Testing ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
In Vivo Models

Abstract Intrinsic factors such as genetic lesions, anti-apoptotic proteins, and aberrant signaling networks within leukemia cells have long been the main focus of chronic lymphocytic leukemia (CLL) research. However, over the past decade, it became increasingly clear that external signals from the leukemia microenvironment make pivotal contributions to disease progression in CLL and other B-cell malignancies. Consequently, increasing emphasis is now placed on exploring and targeting the CLL microenvironment. This review highlights critical cellular and molecular pathways of CLL-microenvironment cross-talk. In vitro and in vivo models for studying the CLL microenvironment are discussed, along with their use in searching for therapeutic targets and in drug testing. Clinically, CXCR4 antagonists and small-molecule antagonists of B cell receptor (BCR)-associated kinases (spleen tyrosine kinase [Syk], Bruton's tyrosine kinase [Btk], and PI3Kδ) are the most advanced drugs for targeting specific interactions between CLL cells and the miocroenvironment. Preclinical and first clinical evidence suggests that high-risk CLL patients can particularly benefit from these alternative agents. These findings indicate that interplay between leukemia-inherent and environmental factors, nature and nurture determines disease progression in CLL.

scholarly journals Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

2018 ◽  
Vol 215 (2) ◽  
pp. 681-697 ◽  
Author(s):  
Erika Tissino ◽  
Dania Benedetti ◽  
Sarah E.M. Herman ◽  
Elisa ten Hacken ◽  
Inhye E. Ahn ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Independent Manner ◽  
Btk Inhibitor

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.

Relationship between in vitro and in vivo Radiosensitivity of Lymphocytes in Chronic Lymphocytic Leukemia

1988 ◽  
Vol 80 (3) ◽  
pp. 129-133 ◽  
Author(s):  
Robert Schrek ◽  
William R. Best ◽  
Stefano Stefani
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia
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