B-cell Acute Lymphoblastic Leukemia in Patients with Chronic Lymphocytic Leukemia Treated with Lenalidomide

Blood ◽  
2020 ◽  
Author(s):  
Moritz Fürstenau ◽  
Anna Maria Fink ◽  
Anke Schilhabel ◽  
Jonathan Weiss ◽  
Sandra Robrecht ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
De Novo ◽  
Cell Clone ◽  
Biological Effects ◽  
Lymphoblastic Leukemia ◽  
Cohort Analysis ◽  
Cell Receptor ◽  
Lymphocytic Leukemia

The placebo controlled CLLM1 trial evaluated the efficacy of lenalidomide maintenance treatment in patients with high-risk chronic lymphocytic leukemia (CLL) in first remission after chemoimmunotherapy (CIT). Upon observation of three cases with acute lymphoblastic leukemia (ALL) in overall 56 lenalidomide treated patients (5.4%), the study treatment was prematurely stopped. Using next generation sequencing of B cell and T cell receptor (TR) rearrangements, we here report common clonal B cell ancestry between CLL and ALL in one of those three patients, in whom both diseases shared the same VDJ- as well as crosslineage TR rearrangements. Chromosomal/mutation analyses indicated that in this patient the ALL developed from a common B cell precursor which lacks genomic lesions acquired in the CLL subclone, but shares a BIRC3 frameshift deletion (p.L421fs*). In two cases we found independent IGH rearrangements indicating de novo ALL development from a different B cell clone. A retrospective cohort analysis of >1600 CLL patients treated with first-line CIT in previously reported phase 2-3 studies of the German CLL study group, yielded a significantly lower cumulative incidence of ALL at 12.6 cases/100,000 patient years, compared to 1345.5 cases/100,000 patient-years observed in the lenalidomide arm of the CLLM1 study. Given our results and increasing knowledge on the biological effects of lenalidomide in bone marrow precursor cells, we discuss the potential involvement of lenalidomide in the pathogenesis of ALL in CLL patients.

Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia

2019 ◽  
Vol 44 (4) ◽  
pp. 499-509 ◽  
Author(s):  
Ayşegül Dalmızrak ◽  
Nur Selvi Günel ◽  
Burçin Tezcanlı Kaymaz ◽  
Fahri Şahin ◽  
Güray Saydam ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Signaling Pathways ◽  
Cell Lines ◽  
B Lymphocyte ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Protein Expressions ◽  
Apoptotic Effect

AbstractObjectivesRituximab is a monoclonal antibody that targets the B-lymphocyte surface antigen CD20. It is used in the treatment of some diseases including B-cell chronic lymphocytic leukemia (B-CLL). There are a lot of data regarding effect of Rituximab on lymphoma cells. But, there is no satisfactory information about the effect of Rituximab on the signaling pathways in leukemia cells. In this study, it was aimed to understand the effect of Rituximab on JAK-STAT and NF-κB signaling pathways in B-cell acute lymphoblastic leukemia (B-ALL) and B-CLL.Material and methodsApoptotic effect of Rituximab in the TANOUE (B-ALL) and EHEB (B-CLL) cell lines were evaluated by using the Annexin V method. mRNA expression levels of STAT3 and RelA were analysed by quantitative RT-PCR (Q-PCR). Alterations in STAT3 and RelA protein expressions were detected by using a chromogenic alkaline phosphatase assay after Western Blotting.ResultsRituximab had no apoptotic effect on both cell lines. Complement-mediated cytotoxicity was only detected in EHEB cells. mRNA and protein expressions of STAT3 and RelA genes were decreased following Rituximab treatment.ConclusionOur preliminary results suggest that the use of Rituximab might be effective in B-ALL though both signaling pathways.

scholarly journals Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia

Blood ◽  
2017 ◽  
Vol 130 (21) ◽  
pp. 2317-2325 ◽  
Author(s):  
Karen Thudium Mueller ◽  
Shannon L. Maude ◽  
David L. Porter ◽  
Noelle Frey ◽  
Patricia Wood ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Efficacy ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Cellular Kinetics ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Kinetics Of

Key Points Tisagenlecleucel (CTL019) has demonstrated clinical efficacy in relapsed/refractory B-cell ALL and CLL. The cellular kinetic profile of tisagenlecleucel was consistent across the 2 diseases, with higher exposure in responding vs nonresponding patients.

scholarly journals The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4656-4666 ◽  
Author(s):  
David M. Lucas ◽  
Ryan B. Edwards ◽  
Gerard Lozanski ◽  
Derek A. West ◽  
Jungook D. Shin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Translational Inhibition

Abstract Therapeutic options for advanced B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are limited. Available treatments can also deplete T lymphocytes, leaving patients at risk of life-threatening infections. In the National Cancer Institute cell line screen, the structurally unique natural product silvestrol produces an unusual pattern of cytotoxicity that suggests activity in leukemia and selectivity for B cells. We investigated silvestrol efficacy using primary human B-leukemia cells, established B-leukemia cell lines, and animal models. In CLL cells, silvestrol LC50 (concentration lethal to 50%) is 6.9 nM at 72 hours. At this concentration, there is no difference in sensitivity of cells from patients with or without the del(17p13.1) abnormality. In isolated cells and whole blood, silvestrol is more cytotoxic toward B cells than T cells. Silvestrol causes early reduction in Mcl-1 expression due to translational inhibition with subsequent mitochondrial damage, as evidenced by reactive oxygen species generation and membrane depolarization. In vivo, silvestrol causes significant B-cell reduction in Eμ-Tcl-1 transgenic mice and significantly extends survival of 697 xenograft severe combined immunodeficient (SCID) mice without discernible toxicity. These data indicate silvestrol has efficacy against B cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias.

scholarly journals Transformation of chronic lymphocytic leukemia into B-cell acute lymphoblastic leukemia

Blood ◽  
2018 ◽  
Vol 131 (11) ◽  
pp. 1258-1261 ◽  
Author(s):  
Seongseok Yun ◽  
Ling Zhang ◽  
Manish R. Patel ◽  
Todd C. Knepper ◽  
Julio C. Chavez ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

Geldanamycin-induced Lyn dissociation from aberrant Hsp90-stabilized cytosolic complex is an early event in apoptotic mechanisms in B-chronic lymphocytic leukemia

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4665-4674 ◽  
Author(s):  
Livio Trentin ◽  
Martina Frasson ◽  
Arianna Donella-Deana ◽  
Federica Frezzato ◽  
Mario A. Pagano ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Cell Receptor ◽  
Hsp90 Inhibitor ◽  
Lymphocytic Leukemia ◽  
Early Event ◽  
Downstream Signaling ◽  
Transient Interactions

Abstract Lyn, a tyrosine kinase belonging to the Src family, plays a key role as a switch molecule that couples the B-cell receptor to downstream signaling. In B-CLL cells, Lyn is overexpressed, anomalously present in the cytosol, and displays a high constitutive activity, compared with normal B lymphocytes. The aim of this work was to gain insights into the molecular mechanisms underlying these aberrant properties of Lyn, which have already been demonstrated to be related to defective apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Herein, Lyn is described to be in an active conformation as integral component of an aberrant cytosolic 600-kDa multiprotein complex in B-CLL cells, associated with several proteins, such as Hsp90 through its catalytic domain, and HS1 and SHP-1L through its SH3 domain. In particular, Hsp90 appears tightly bound to cytosolic Lyn (CL), thus stabilizing the aberrant complex and converting individual transient interactions into stable ones. We also demonstrate that treatment of B-CLL cells with geldanamycin, an Hsp90 inhibitor already reported to induce cell death, is capable of dissociating the CL complex in the early phases of apoptosis and thus inactivating CL itself. These data identify the CL complex as a potential target for therapy in B-CLL.

scholarly journals Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells

2021 ◽  
Author(s):  
Sarah Wilmore ◽  
Karly-Rai Rogers-Broadway ◽  
Joe Taylor ◽  
Elizabeth Lemm ◽  
Rachel Fell ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mrna Translation ◽  
Cell Receptor ◽  
Memory B Cells ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Mrna Levels ◽  
Mrna Stabilization

AbstractSignaling via the B-cell receptor (BCR) is a key driver and therapeutic target in chronic lymphocytic leukemia (CLL). BCR stimulation of CLL cells induces expression of eIF4A, an initiation factor important for translation of multiple oncoproteins, and reduces expression of PDCD4, a natural inhibitor of eIF4A, suggesting that eIF4A may be a critical nexus controlling protein expression downstream of the BCR in these cells. We, therefore, investigated the effect of eIF4A inhibitors (eIF4Ai) on BCR-induced responses. We demonstrated that eIF4Ai (silvestrol and rocaglamide A) reduced anti-IgM-induced global mRNA translation in CLL cells and also inhibited accumulation of MYC and MCL1, key drivers of proliferation and survival, respectively, without effects on upstream signaling responses (ERK1/2 and AKT phosphorylation). Analysis of normal naïve and non-switched memory B cells, likely counterparts of the two main subsets of CLL, demonstrated that basal RNA translation was higher in memory B cells, but was similarly increased and susceptible to eIF4Ai-mediated inhibition in both. We probed the fate of MYC mRNA in eIF4Ai-treated CLL cells and found that eIF4Ai caused a profound accumulation of MYC mRNA in anti-IgM treated cells. This was mediated by MYC mRNA stabilization and was not observed for MCL1 mRNA. Following drug wash-out, MYC mRNA levels declined but without substantial MYC protein accumulation, indicating that stabilized MYC mRNA remained blocked from translation. In conclusion, BCR-induced regulation of eIF4A may be a critical signal-dependent nexus for therapeutic attack in CLL and other B-cell malignancies, especially those dependent on MYC and/or MCL1.

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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