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 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

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 Standardized flow cytometry for highly sensitive MRD measurements in B-cell acute lymphoblastic leukemia

Blood ◽  
2017 ◽  
Vol 129 (3) ◽  
pp. 347-357 ◽  
Author(s):  
Prisca Theunissen ◽  
Ester Mejstrikova ◽  
Lukasz Sedek ◽  
Alita J. van der Sluijs-Gelling ◽  
Giuseppe Gaipa ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Flow Cytometric ◽  
Highly Sensitive ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia

Key Points Standardized flow cytometry allows highly sensitive MRD measurements in virtually all BCP-ALL patients. If sufficient cells are measured (>4 million), flow cytometric MRD analysis is at least as sensitive as current PCR-based MRD methods.

scholarly journals Progenitor B-1 B-cell acute lymphoblastic leukemia is associated with collaborative mutations in 3 critical pathways

2017 ◽  
Vol 1 (20) ◽  
pp. 1749-1759 ◽  
Author(s):  
Sheryl M. Gough ◽  
Liat Goldberg ◽  
Marbin Pineda ◽  
Robert L. Walker ◽  
Yuelin J. Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
B Cells ◽  
B Cell ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Lymphoblastic Leukemia ◽  
Critical Pathways ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia

Key Points An NUP98-PHF23 fusion collaborates with acquired Bcor and Jak/Stat mutations to produce a pro–B-1 ALL. Gene expression profile of murine pro–B-1 ALL resembles that of a subset of human ALL, suggesting some human ALLs arise from pro–B-1 B cells.

scholarly journals BCR-ABL1 gene rearrangement as a subclonal change in ETV6-RUNX1–positive B-cell acute lymphoblastic leukemia

2016 ◽  
Vol 1 (2) ◽  
pp. 132-138 ◽  
Author(s):  
Karen A. Dun ◽  
Rob Vanhaeften ◽  
Tracey J. Batt ◽  
Louise A. Riley ◽  
Giuseppe Diano ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Tyrosine Kinase Inhibitors ◽  
Gene Rearrangement ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Rare Occurrence ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia

Key Points BCR-ABL1 rearrangement as a subclonal change in ETV6-RUNX1–positive B-ALL is a rare occurrence not previously reported. The prognosis of this rare subclonal change has not been determined, yet inclusion of tyrosine kinase inhibitors in treatment is ubiquitous.

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.

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 HDAC3 functions as a positive regulator in Notch signal transduction

2020 ◽  
Vol 48 (7) ◽  
pp. 3496-3512 ◽  
Author(s):  
Francesca Ferrante ◽  
Benedetto Daniele Giaimo ◽  
Marek Bartkuhn ◽  
Tobias Zimmermann ◽  
Viola Close ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Acute Lymphoblastic Leukemia ◽  
Chronic Lymphocytic Leukemia ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Loss Of Function ◽  
Local Reduction ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Dependent Mechanism

Abstract Aberrant Notch signaling plays a pivotal role in T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL). Amplitude and duration of the Notch response is controlled by ubiquitin-dependent proteasomal degradation of the Notch1 intracellular domain (NICD1), a hallmark of the leukemogenic process. Here, we show that HDAC3 controls NICD1 acetylation levels directly affecting NICD1 protein stability. Either genetic loss-of-function of HDAC3 or nanomolar concentrations of HDAC inhibitor apicidin lead to downregulation of Notch target genes accompanied by a local reduction of histone acetylation. Importantly, an HDAC3-insensitive NICD1 mutant is more stable but biologically less active. Collectively, these data show a new HDAC3- and acetylation-dependent mechanism that may be exploited to treat Notch1-dependent leukemias.

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