scholarly journals Opposing regulation of BIM and BCL2 controls glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells

Blood ◽  
2015 ◽  
Vol 125 (2) ◽  
pp. 273-283 ◽  
Author(s):  
Duohui Jing ◽  
Vivek A. Bhadri ◽  
Dominik Beck ◽  
Julie A. I. Thoms ◽  
Nurul A. Yakob ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Glucocorticoid Receptor ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Intronic Region ◽  
Key Points ◽  
Pediatric All ◽  
Induced Apoptosis

Key Points The glucocorticoid receptor coordinately regulates the antiapoptotic BCL2 and proapoptotic BIM genes in pediatric ALL cells in vivo. GR binding at a novel intronic region is associated with BIM transcription and dexamethasone sensitivity in pediatric ALL cells in vivo.

Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition

Blood ◽  
2010 ◽  
Vol 116 (16) ◽  
pp. 3013-3022 ◽  
Author(s):  
Petra S. Bachmann ◽  
Rocco G. Piazza ◽  
Mary E. Janes ◽  
Nicholas C. Wong ◽  
Carwyn Davies ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Histone Deacetylase ◽  
Cpg Island ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Epigenetic Silencing ◽  
Glucocorticoid Resistance ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All

Abstract Glucocorticoids play a critical role in the therapy of lymphoid malignancies, including pediatric acute lymphoblastic leukemia (ALL), although the mechanisms underlying cellular resistance remain unclear. We report glucocorticoid resistance attributable to epigenetic silencing of the BIM gene in pediatric ALL biopsies and xenografts established in immune-deficient mice from direct patient explants as well as a therapeutic approach to reverse resistance in vivo. Glucocorticoid resistance in ALL xenografts was consistently associated with failure to up-regulate BIM expression after dexamethasone exposure despite confirmation of a functional glucocorticoid receptor. Although a comprehensive assessment of BIM CpG island methylation revealed no consistent changes, glucocorticoid resistance in xenografts and patient biopsies significantly correlated with decreased histone H3 acetylation. Moreover, the histone deacetylase inhibitor vorinostat relieved BIM repression and exerted synergistic antileukemic efficacy with dexamethasone in vitro and in vivo. These findings provide a novel therapeutic strategy to reverse glucocorticoid resistance and improve outcome for high-risk pediatric ALL.

A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia

Blood ◽  
2014 ◽  
Vol 124 (9) ◽  
pp. 1434-1444 ◽  
Author(s):  
Anthony V. Moorman ◽  
Amir Enshaei ◽  
Claire Schwab ◽  
Rachel Wade ◽  
Lucy Chilton ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Risk Stratification ◽  
Lymphoblastic Leukemia ◽  
Genomic Data ◽  
Genetic Profile ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Key Points ◽  
Pediatric All ◽  
Good Risk

Key Points Integrating cytogenetic and genomic data in pediatric ALL reveals 2 subgroups with different outcomes independent of other risk factors. A total of 75% of children on UKALL2003 had a good-risk genetic profile, which predicted an EFS and OS of 94% and 97% at 5 years.

In-Vitro Efficacy of the Deoxyguanoside Analogs Forodesine (BCX- 1777) and ARA-G in Pediatric Acute Lymphoblastic Leukemia Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1925-1925
Author(s):  
Irene Homminga ◽  
Christian M Zwaan ◽  
Chantal Y. Manz ◽  
Shanta Bantia ◽  
Cynthia Parker ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Nucleotide Synthesis ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Lc50 Value ◽  
Pediatric All

Abstract Purine nucleotide phosphorylase (PNP) deficiency in humans is associated with elevated dGuo plasma levels. This results in the intra-cellular conversion of dGuo into dGTP, following 3 consecutive kinase steps and depletion of T-cells resulting in immune deficiency. This T-cell toxicity provided the rationale for the development of deoxyguanosine analogues as potential therapeutic compounds for T-cell malignancies. Forodesine (BCX-1777; BioCryst-Mundipharma) is an efficient blocker of PNP activity. Forodesine facilitates the conversion of dGuo into dGTP raising the intracellular dGTP pool. AraG (9-b-D-arabinofuranosyl-guanine) is a compound that is resistant to PNP-mediated degradation resulting in phosphorylation of AraG into AraGTP. AraGTP becomes incorporated in the DNA and blocks DNA synthesis resulting in apoptosis. In a phase II clinical trial, the AraG prodrug Nelarabine enforced a complete remission rate of 55% for pediatric T-ALL patients at 1st relapse. (Berg, JCO 2005). Clinical data of forodesine treatment in pediatric ALL patients are not yet available. The cytotoxic effect of Forodesine was investigated on primary leukemia cells from newly diagnosed pediatric acute lymphoblastic leukemia (ALL) patients in-vitro. Cells were incubated with a fixed concentration of Forodesine (1μM) in the presence of increasing concentrations of dGuo (0.001–50μM). The dGTP levels under conditions where PNPactivity was completely blocked was monitored. Incubation of primary leukemic cells obtained from 6 pediatric ALL patients (4 T-ALL, 2 B-ALL) with 10μM dGuo results in rapid dGuo degradation (t½<4hrs) by the PNP enzyme that is completely abolished by the addition of 1μM of Forodesine. Cells consequently accumulate dGTP levels upon Forodesine treatment to a median 7.9 (range 0.5–378 fold) that is comparable between T-ALL (n=31) and B-ALL (n=11) patient samples. This reflects equal intrinsic ability of de-novo nucleotide synthesis for both T-ALL and B-ALL cells. In accordance with T-cell selective toxicity, T-ALL cells were more sensitive to Forodesine/ dGuo treatment (median T-ALL LC50 value: 1.1μM dGuo/1μM Forodesine, n=27, p=0.001) compared to B-ALL cells, which had a median LC50 value of 8.8μM dGuo/1μM Forodesine (n=30). All patients that responded demonstrated dGTP accumulation (1.5– 222.1 fold), but the magnitude of dGTP accumulation did not relate to Forodesine/dGuo toxicity. Studying in-vitro responsiveness to AraG, T-ALL cells were more sensitive compared to B-ALL cells (p=0.0002) with a median AraG LC50 value of 20.5μM for T-ALL samples (n=24) versus 48.3μM for B-ALL samples (n=20). However, TELAML1 negative B-ALL cases were sensitive to AraG where as TELAML1 positive B-ALL cases were remarkable insensitive to AraG treatment (median LC50 value >50μM, n=9). No correlation was identified between in-vitro Forodesine/dGuo and AraG cytotoxicities. Most patient samples that displayed AraG resistance still responded to Forodesine/dGuo treatment. In contrast, AraG cytotoxicity strongly correlated with AraC cytotoxicity (r2=0.71, p<0.0001). In conclusion, T-ALL cells are sensitive to Forodesine/dGuo treatment in-vitro in contrast to B-ALL cells that have nearly 8 fold higher LC50 values. In-vitro Forodesine mediated cytotoxicity seems more potent in pediatric ALL than AraG treatment. Resistance to AraG treatment does not preclude responsiveness to Forodesine treatment and vice versa, indicating that Forodesine and AraG rely on different cellular mechanisms for cytotoxicity.

scholarly journals Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 365
Author(s):  
Carina Colturato-Kido ◽  
Rayssa M. Lopes ◽  
Hyllana C. D. Medeiros ◽  
Claudia A. Costa ◽  
Laura F. L. Prado-Souza ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clinical Problem ◽  
Jurkat Cells ◽  
Leukemia Cells ◽  
Peripheral Mononuclear Blood ◽  
Induced Apoptosis ◽  
Cure Rates

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a “double-edged sword” contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL.

Role of Matrix Metalloproteinase MMP-2, MMP-9 and Tissue Inhibitor of Metalloproteinase (TIMP-1) in Clinical Progression of Pediatric Acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Maha Saleh ◽  
Mohamed Khalil ◽  
Mona S. Abdellateif ◽  
Emad Ebeid ◽  
Eman Z. Kandeel
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Count ◽  
Cancer Progression ◽  
Lymphoblastic Leukemia ◽  
Multivariate Logistic Regression Analysis ◽  
Blast Cell ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All

Abstract Background: Matrix metalloproteinases (MMPs) play a crucial role in cancer progression and metastasis, however their role in pediatric Acute lymphoblastic leukemia (ALL) is still unrevealed.Methods: The diagnostic, prognostic and predictive value of tissue inhibitor of metalloproteinase (TIMP-1), MMP-2, MMP-9 and CD34+CD38- CSCs were assessed in bone marrow (BM) samples of 76 ALL children using Flow Cytometry analysis. Results: There was a significant increase in TIMP-1 [1.52 (0.41-10) versus 0.91(0.6-1.12); respectively, P<0.001], and CSCs CD84+CD38- [1 (0.03-18.6) versus 0.3 (0.01-1.1), P<0.001] expression in ALL patients compared to controls. While there were no significant differences regarding MMP-2 and MMP-9 expression between the two groups. The sensitivity, specificity, AUC of MMP-2 were (80.3%, 53.3% and 0.568, P=0.404), and that of MMP-9 were (53.9%, 40% and 0.660, P=0.053). While that of TIMP-1 were (78.9%, 100% and 0.892, P<0.001), and that of CSCs CD34+ CD38- were (78.9%, 73.3% and 0.855, P<0.001). There was a significant association between MMP-2 overexpression and MRD at day-15, increased BM blast cell count at diagnosis and at day-15, (P=0.020, P=0.047 and P=0.001). Increased TIMP-1 expression associated with the high-risk disease (P<0.001), increased BM blast cell count at diagnosis and at day-15 (P=0.033 and P=0.001), as well as MRD at day 15 and day 42 (P<0.001 for both). CD34+CD38- CSCs associated with MRD at day-15, increased BM blast cell count at diagnosis and at day-15 (P=0.015, P=0.005 and P=0.003). TIMP-1 overexpression associated with shorter DFS and OS rates (P=0.009 and P=0.048). Multivariate logistic regression analysis showed that both TIMP-1 [OR: 4.224, P=0.046], and CD34+CD38- CSCs [OR: 6.873, P=0.005] are independent diagnostic factors for pediatric ALL.Conclusion: TIMP-1 and CD34+CD38- CSCs could be useful independent diagnostic markers for pediatric ALL. Also, TIMP-1 is a promising prognostic marker for poor outcome of the patients.

scholarly journals Inhibition of telomerase using BIBR1532 enhances doxorubicin-induced apoptosis in pre-B acute lymphoblastic leukemia cells

Hematology ◽  
2017 ◽  
Vol 22 (6) ◽  
pp. 330-340 ◽  
Author(s):  
Davood Bashash ◽  
Mohadeseh Zareii ◽  
Ava Safaroghli-Azar ◽  
Mir Davood Omrani ◽  
Seyed H. Ghaffari
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Induced Apoptosis

scholarly journals Acute lymphoblastic leukemia cells that survive combination chemotherapy in vivo remain sensitive to allogeneic immune effects

2011 ◽  
Vol 35 (6) ◽  
pp. 800-807 ◽  
Author(s):  
Johan Jansson ◽  
Yu-Chiao Hsu ◽  
Igor I. Kuzin ◽  
Andrew Campbell ◽  
Craig A. Mullen
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Combination Chemotherapy ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells

Improving pneumococcal vaccination rates in pediatric acute lymphoblastic leukemia/lymphoblastic lymphoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18666-e18666
Author(s):  
Simone Chang ◽  
Alexandra Cheerva ◽  
Michael Angelo Huang ◽  
Kerry McGowan ◽  
Esther E Knapp ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Pneumococcal Vaccination ◽  
Vaccination Rate ◽  
Lymphoblastic Lymphoma ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Vaccination Rates ◽  
Targeted Interventions ◽  
Pediatric All

e18666 Background: Pediatric Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma (ALL/LLy) is the most common pediatric cancer. Invasive pneumococcal disease (IPD) is prevalent in this population and the Centers for Disease Control and Prevention recommends pneumococcal vaccination to decrease morbidity and mortality. Despite these recommendations, vaccination rates remain low and the incidence of IPD among children with hematologic malignancy is significantly higher compared to the average pediatric population. An interventional study was designed to improve the vaccination rate and reduce the incidence of IPD in our institution. Methods: A plan-do-study-act (PDSA) model of quality improvement (QI) was used. Chart review at our institute was done for the 6-month period of January 2020 - June 2020 and baseline rates for pneumococcal polysaccharide (PPSV23) vaccination were calculated. Patients were included if they were ≥ 2 years old, diagnosed with ALL/LLy, and undergoing maintenance. A multidisciplinary team performed the root cause analysis. Immunization records were obtained and reviewed and targeted interventions were implemented. The interventions used are outlined in Table. The percentage of pediatric ALL/LLy patients per month in maintenance who received age-appropriate pneumococcal vaccinations was monitored before and after the interventions. Results: Analysis of the 6-month retrospective cohort (n=36) showed a baseline vaccination rate of 5.5%. During the subsequent 6-month phase with interventions, 40 patients were prospectively enrolled. Demographics showed a mean age of 10.2 years (range, 2-21) and a predominantly male (66.7%) cohort. B-cell ALL/LLy comprised the majority (78.9%); the rest included T-cell ALL/LLy and mixed phenotype acute leukemia. As seen in Table, the percentage receiving at least 1 pneumococcal vaccine increased from 5.5% to 84.8% over the first 3 months, this plateaued around 81%. Completion of the series mirrored this and increased to 74.2%. Pre-visit planning and cues proved to be the most helpful interventions. Conclusions: Use of a PDSA model successfully improved pneumococcal vaccination rates in the pediatric ALL/LLy population. We suggest these results can be achieved with planning and implementation of the outlined interventions. [Table: see text]

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