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[PMID]: 28456746
[Au] Autor:Carretta M; de Boer B; Jaques J; Antonelli A; Horton SJ; Yuan H; de Bruijn JD; Groen RWJ; Vellenga E; Schuringa JJ
[Ad] Address:Department of Experimental Hematology, Cancer Research Centre Groningen, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
[Ti] Title:Genetically engineered mesenchymal stromal cells produce IL-3 and TPO to further improve human scaffold-based xenograft models.
[So] Source:Exp Hematol;51:36-46, 2017 07.
[Is] ISSN:1873-2399
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Recently, NOD-SCID IL2Rγ (NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or Matrigel to mimic the human bone marrow (BM) microenvironment. This approach allowed the engraftment of leukemic samples that failed to engraft in NSG mice without humanized niches and resulted in a better preservation of leukemic stem cell self-renewal properties. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human interleukin-3 (IL-3) and thrombopoietin (TPO). In vitro, these IL-3- and TPO-producing MSCs were superior in expanding human cord blood (CB) CD34 hematopoietic stem/progenitor cells. MLL-AF9-transduced CB CD34 cells could be transformed efficiently along myeloid or lymphoid lineages on IL-3- and TPO-producing MSCs. In vivo, these genetically engineered MSCs maintained their ability to differentiate into bone, adipocytes, and other stromal components. Upon transplantation of MLL-AF9-transduced CB CD34 cells, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) developed in engineered scaffolds, in which a significantly higher percentage of myeloid clones was observed in the mouse compartments compared with previous models. Engraftment of primary AML, B-cell ALL, and biphenotypic acute leukemia (BAL) patient samples was also evaluated, and all patient samples could engraft efficiently; the myeloid compartment of the BAL samples was better preserved in the human cytokine scaffold model. In conclusion, we show that we can genetically engineer the ectopic human BM microenvironment in a humanized scaffold xenograft model. This approach will be useful for functional study of the importance of niche factors in normal and malignant human hematopoiesis.
[Mh] MeSH terms primary: Cell Differentiation
Genetic Engineering
Interleukin-3
Mesenchymal Stromal Cells/metabolism
Stem Cell Niche
Thrombopoietin
Tissue Scaffolds/chemistry
[Mh] MeSH terms secundary: Animals
Disease Models, Animal
Heterografts
Humans
Interleukin-3/biosynthesis
Interleukin-3/genetics
Leukemia, Myeloid, Acute/genetics
Leukemia, Myeloid, Acute/metabolism
Mesenchymal Stem Cell Transplantation
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Transplantation
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism
Thrombopoietin/biosynthesis
Thrombopoietin/genetics
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (IL3 protein, human); 0 (Interleukin-3); 9014-42-0 (Thrombopoietin)
[Em] Entry month:1709
[Cu] Class update date: 180224
[Lr] Last revision date:180224
[Js] Journal subset:IM
[Da] Date of entry for processing:170501
[St] Status:MEDLINE

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[PMID]: 29385376
[Au] Autor:Park JH; Rivière I; Gonen M; Wang X; Sénéchal B; Curran KJ; Sauter C; Wang Y; Santomasso B; Mead E; Roshal M; Maslak P; Davila M; Brentjens RJ; Sadelain M
[Ad] Address:From the Leukemia Service, Department of Medicine (J.H.P., C.S., P.M., R.J.B.), the Michael G. Harris Cell Therapy and Cell Engineering Facility (I.R., X.W., B. Sénéchal, Y.W.), the Center for Cell Engineering (J.H.P., I.R., X.W., R.J.B., M.S.), and the Departments of Epidemiology and Biostatistics
[Ti] Title:Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia.
[So] Source:N Engl J Med;378(5):449-459, 2018 02 01.
[Is] ISSN:1533-4406
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients. METHODS: We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics. RESULTS: A total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden. CONCLUSIONS: In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).
[Mh] MeSH terms primary: Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
Receptors, Antigen, T-Cell/therapeutic use
T-Lymphocytes/immunology
[Mh] MeSH terms secundary: Adult
Aged
Cytokines/metabolism
Follow-Up Studies
Humans
Middle Aged
Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality
Recurrence
Remission Induction
Survival Analysis
[Pt] Publication type:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (CD19-specific chimeric antigen receptor); 0 (Cytokines); 0 (Receptors, Antigen, T-Cell)
[Em] Entry month:1802
[Cu] Class update date: 180222
[Lr] Last revision date:180222
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:180201
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1709919

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[PMID]: 29254309
[Au] Autor:Tahir IM; Iqbal T; Jamil A; Saqib M
[Ad] Address:Pharmaceutical Research Lab, Department of Biochemistry, University of Agriculture, Faisalabad-Pakistan.
[Ti] Title:Association of BCL-2 with oxidative stress and total antioxidant status in pediatric acute lymphoblastic leukemia.
[So] Source:J Biol Regul Homeost Agents;31(4):1023-1027, 2017 Oct-Dec.
[Is] ISSN:0393-974X
[Cp] Country of publication:Italy
[La] Language:eng
[Ab] Abstract:B-Cell Lymphoma protein-2 (BCL-2) is one of the most studied proteins with substantial regulatory potential for both apoptosis and autophagy. BCL-2 confer chemoresistance through influencing cancer pathophysiology. Serum level of lactate dehydrogenase (LDH) predicts increased anaerobic glycolysis and is associated with metabolic modulation in cancer cells. In the present research, the interplay of BCL-2, total oxidative status (TOS) and LDH was investigated in patients with acute lymphoblastic leukemia (ALL). The studied parameters, BCL-2 protein (p less than 0.001), TOS (p less than 0.001) and LDH (p less than 0.001) were significantly elevated in the ALL group compared to the normal group (N-group). However, the total antioxidant status (TAS) was reduced significantly (p less than 0.01) in ALL patients. In the ALL group, the TOS had significant negative correlation with TAS (p less than 0.01). Furthermore, non-significant positive correlations were found between BCL-2 and LDH, BCL-2 and TAS and LDH and TAS (each with; p>0.05). However, a negative non-significant correlation was observed between BCL-2 and TOS and LDH and TOS (each with; p>0.05).
[Mh] MeSH terms primary: Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Gene Expression Regulation, Leukemic
L-Lactate Dehydrogenase/genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
Proto-Oncogene Proteins c-bcl-2/genetics
[Mh] MeSH terms secundary: Adolescent
Child
Child, Preschool
Female
Humans
Infant
L-Lactate Dehydrogenase/blood
Male
Oxidation-Reduction
Oxidative Stress
Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
Proto-Oncogene Proteins c-bcl-2/blood
Signal Transduction
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (BCL2 protein, human); 0 (Proto-Oncogene Proteins c-bcl-2); EC 1.1.1.27 (L-Lactate Dehydrogenase)
[Em] Entry month:1802
[Cu] Class update date: 180222
[Lr] Last revision date:180222
[Js] Journal subset:IM
[Da] Date of entry for processing:171220
[St] Status:MEDLINE

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[PMID]: 29194562
[Au] Autor:Sutton R; Venn NC; Law T; Boer JM; Trahair TN; Ng A; Den Boer ML; Dissanayake A; Giles JE; Dalzell P; Mayoh C; Barbaric D; Revesz T; Alvaro F; Pieters R; Haber M; Norris MD; Schrappe M; Dalla Pozza L; Marshall GM
[Ad] Address:Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
[Ti] Title:A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B-cell acute lymphoblastic leukaemia in children.
[So] Source:Br J Haematol;180(4):550-562, 2018 02.
[Is] ISSN:1365-2141
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:To prevent relapse, high risk paediatric acute lymphoblastic leukaemia (ALL) is treated very intensively. However, most patients who eventually relapse have standard or medium risk ALL with low minimal residual disease (MRD) levels. We analysed recurrent microdeletions and other clinical prognostic factors in a cohort of 475 uniformly treated non-high risk precursor B-cell ALL patients with the aim of better predicting relapse and refining risk stratification. Lower relapse-free survival at 7 years (RFS) was associated with IKZF1 intragenic deletions (P < 0·0001); P2RY8-CRLF2 gene fusion (P < 0·0004); Day 33 MRD>5 × 10 (P < 0·0001) and High National Cancer Institute (NCI) risk (P < 0·0001). We created a predictive model based on a risk score (RS) for deletions, MRD and NCI risk, extending from an RS of 0 (RS0) for patients with no unfavourable factors to RS2 +  for patients with 2 or 3 high risk factors. RS0, RS1, and RS2 +  groups had RFS of 93%, 78% and 49%, respectively, and overall survival (OS) of 99%, 91% and 71%. The RS provided greater discrimination than MRD-based risk stratification into standard (89% RFS, 96% OS) and medium risk groups (79% RFS, 91% OS). We conclude that this RS may enable better early therapeutic stratification and thus improve cure rates for childhood ALL.
[Mh] MeSH terms primary: Chromosome Deletion
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality
Sequence Deletion
[Mh] MeSH terms secundary: Adolescent
Age Factors
Biomarkers, Tumor
Child
Child, Preschool
Female
Genotype
Humans
Infant
Male
Neoplasm, Residual/diagnosis
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
Prognosis
Proportional Hazards Models
Recurrence
Risk Assessment
Risk Factors
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Biomarkers, Tumor)
[Em] Entry month:1802
[Cu] Class update date: 180221
[Lr] Last revision date:180221
[Js] Journal subset:IM
[Da] Date of entry for processing:171202
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.15056

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[PMID]: 29262503
[Au] Autor:Wang Y; Han ZX; Zhang JC
[Ad] Address:Department of Oncology, Xuzhou Central Hospital of Southeast University, Xuzhou 221000, China.
[Ti] Title:[Effects of bone marrow stromal cells on the chemotherapeutic sensitivity of acute lymphoblastic leukemia cells].
[So] Source:Zhonghua Zhong Liu Za Zhi;39(12):885-890, 2017 Dec 23.
[Is] ISSN:0253-3766
[Cp] Country of publication:China
[La] Language:chi
[Ab] Abstract:To investigate the influences of bone marrow stromal cells, components of extracellular matrix and cytokine secreted by stromal cells on the chemotherapeutic sensitivity of acute lymphoblastic leukemia cells to cytosine arabinoside (Ara-C). The co-culture model of acute lymphoblastic leukemia cell Sup-B15 and bone marrow stromal cell OP9 was constructed. Sup-B15 cells were cultured alone or co-cultured with OP9 cells, inactivated OP9 cells, the conditional medium (CM) of co-cultured OP9 cells and Sup-B15 cells, the CM of OP9 cells alone or Sup-B15 cells alone, respectively. The effects of different concentrations of Ara-C on the proliferation of each Sup-B1 cell group mentioned above were detected by cell counting kit-8 (CCK-8) method. The effects of different concentrations of Ara-C on the apoptosis of each group were detected by flow cytometry (FCM). The expressions of Bcl-2 protein in each group were detected by western blot. The results of CCK-8 test showed that the inhibitory efficiency of Ara-C was in a dose-dependent manner. With different concentrations of Ara-C treatment for 48 hours, the half maximal inhibitory concentrations (IC(50)) of Sup-B15 and OP9 co-cultured group, Sup-B15 and inactivated OP9 co-cultured group were 0.510 and 0.339 µg/ml, respectively, significantly higher than 0.091 µg/ml of Sup-B15 cultured alone group ( <0.05). The IC(50) of CM of Sup-B15 and OP9 co-cultured group was 0.204 µg/ml, significantly higher than 0.087 µg/ml of the CM of OP9 cultured alone group ( <0.05) and 0.097 µg/ml of the CM of Sup-B15 cultured alone group ( <0.05). The results of flow cytometry showed that with 0.10 µg/ml Ara-C treatment for 24 hours, the early apoptotic cell percentages of Sup-B15 and OP9 co-cultured group, Sup-B15 and inactivated OP9 co-cultured group and Sup-B15 cultured alone group were (6.67±2.19) %, (8.95±3.04) % and (20.46±2.63) %, respectively. The early apoptotic cell percentages of Sup-B15 and OP9 co-cultured group, Sup-B15 and inactivated OP9 co-cultured group were significantly lower than that of Sup-B15 cultured alone group ( <0.05). The early apoptotic cell percentages of the CM of Sup-B15 and OP9 co-cultured group, the CM of OP9 cultured alone group and the CM of Sup-B15 cultured alone group were (11.16±2.97)%, (22.08±2.71)% and (19.25±1.57)%, respectively, the former two of which were significantly lower than the last one ( <0.05). The results of western blot showed that the relative expression levels of Bcl-2 protein of Sup-B15 cultured alone group, Sup-B15 and OP9 co-cultured group, Sup-B15 and inactivated OP9 co-cultured group, the CM of Sup-B15 and OP9 co-cultured group, the CM of OP9 cultured alone group and the CM of Sup-B15 cultured alone group were 1.00±0.00, 1.53±0.03, 1.38±0.01, 1.26±0.05, 1.03±0.01 and 0.98±0.02, respectively. The expression levels of bcl-2 protein of three combined groups were significantly higher than that of Sup-B15 cultured alone group ( <0.05). while no statistically significant difference was observed between the CM of OP9 cultured alone group and the CM of Sup-B15 cultured alone group ( >0.05). Bone marrow stromal cell OP9, the components of bone marrow extracellular matrix and cytokine secreted by stromal cells are involved in the induction of the chemotherapeutic resistance of Sup-B15 cells to Ara-C.
[Mh] MeSH terms primary: Antimetabolites, Antineoplastic/pharmacology
Bone Marrow Cells/secretion
Cytarabine/pharmacology
Cytokines/physiology
Cytokines/secretion
Drug Resistance, Neoplasm
Mesenchymal Stromal Cells/secretion
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
[Mh] MeSH terms secundary: Apoptosis
Cell Count
Cell Line, Tumor
Coculture Techniques
Culture Media, Conditioned
Humans
Proto-Oncogene Proteins c-bcl-2
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Antimetabolites, Antineoplastic); 0 (BCL2 protein, human); 0 (Culture Media, Conditioned); 0 (Cytokines); 0 (Proto-Oncogene Proteins c-bcl-2); 04079A1RDZ (Cytarabine)
[Em] Entry month:1802
[Cu] Class update date: 180205
[Lr] Last revision date:180205
[Js] Journal subset:IM
[Da] Date of entry for processing:171221
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.0253-3766.2017.12.002

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[PMID]: 29325246
[Au] Autor:Huang RF; Zhang WY; Liu WP; Zhao S; Ye YX; Sun H; Gao LM; Wang JC; Yang QP
[Ad] Address:Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China.
[Ti] Title:[Diagnostic significance of lymph node core needle biopsy for lymphoproliferative disease: a clinicopathologic study of 1 013 cases].
[So] Source:Zhonghua Bing Li Xue Za Zhi;47(1):19-24, 2018 Jan 08.
[Is] ISSN:0529-5807
[Cp] Country of publication:China
[La] Language:chi
[Ab] Abstract:To study the clinicopathologic features of lymphoproliferative disease by lymph node core needle biopsy(CNB)and to evaluate the diagnostic significance of CNB for lymphoproliferative disease. The annual distribution, entity constitute, clinical finding, gross feature, morphologic change, affiliate study and repeat biopsy diagnosis of 1 013 cases of lymph node CNB diagnosed at West China Hospital of Sichuan University from January 2009 to December 2015 were investigated. (1) Proportion of lymph node CNB in total amount of biopsy specimens increased from 0.2% in 2009 to 0.8% in 2015.(2) The study cohort included 471 lymphomas, 12 atypical lymphoid hyperplasia (ALH), 136 suspected lymphomas, 372 benign lesions, and 22 cases of descriptive diagnoses. The most common types were diffuse large B cell lymphoma and T-lymphoblastic lymphoma. (3) Majority of patients were adolescents and children younger than 20 years or the elderly older than 60 years. 53.1% CNB tumor specimen consisted of ≥4 tissue cores and 40.5% were >2 cm in length. (4) 104 CNB cases with previous history of excision biopsy was included 45 carcinomas(no metastatic carcinoma was found), 32 lymphomas for treatment observation.1/14 suspicious lymphomas, 1/1 ALH and 3/22 cases benign lesions were diagnosed as lymphoma by repeat biopsy respectively. (5) 217 CNB cases were diagnosed as lymphoma by subsequent CNB (70), or subsequent excision biopsy (147) including 78.5%(73/93) suspected lymphomas, 5/7 ALH and 32.3%(20/62)benign lesions. Lymph node CNB has certain clinical indications, although limited for the diagnosis of lymphoproliferative disorders. Suspected lymphomas and ALH diagnosed by CNB should be followed by repeat tissue biopsy. For the benign lesions by CNB it does not rule out additional biopsy to further investigate the lesion.
[Mh] MeSH terms primary: Lymph Nodes/pathology
Lymphoma/pathology
[Mh] MeSH terms secundary: Adolescent
Adult
Aged
Biopsy, Large-Core Needle
Carcinoma/pathology
Child
China
Humans
Hyperplasia/pathology
Lymphoma, B-Cell/pathology
Lymphoma, Non-Hodgkin
Middle Aged
Precancerous Conditions/pathology
Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
Retrospective Studies
Young Adult
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180202
[Lr] Last revision date:180202
[Js] Journal subset:IM
[Da] Date of entry for processing:180112
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.0529-5807.2018.01.005

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[PMID]: 29303717
[Au] Autor:Yaqub F
[Ti] Title:2017: a year in review.
[So] Source:Lancet;390(10114):2753-2754, 2018 12 23.
[Is] ISSN:1474-547X
[Cp] Country of publication:England
[La] Language:eng
[Mh] MeSH terms primary: Armed Conflicts
Child Nutrition Disorders/epidemiology
Cholera/epidemiology
Epidemics
Human Rights
Immunotherapy, Adoptive/methods
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy
Refugees
Sex Offenses
Sexual Harassment
[Mh] MeSH terms secundary: Bangladesh
Child, Preschool
China
Economic Recession
Ethiopia/epidemiology
Food Supply
Health Policy
Humans
Myanmar
Nuclear Weapons
Politics
Somalia/epidemiology
T-Lymphocytes/transplantation
Transplantation, Autologous
United States
Venezuela
World Health Organization
Yemen/epidemiology
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180117
[Lr] Last revision date:180117
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:180106
[St] Status:MEDLINE

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[PMID]: 27777238
[Au] Autor:Tasian SK; Teachey DT; Li Y; Shen F; Harvey RC; Chen IM; Ryan T; Vincent TL; Willman CL; Perl AE; Hunger SP; Loh ML; Carroll M; Grupp SA
[Ad] Address:Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.
[Ti] Title:Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia.
[So] Source:Blood;129(2):177-187, 2017 01 12.
[Is] ISSN:1528-0020
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Philadelphia chromosome (Ph)-like B-cell acute lymphoblastic leukemia (Ph-like ALL) is associated with activated JAK/STAT, Abelson kinase (ABL), and/or phosphatidylinositol 3-kinase (PI3K) signaling and poor clinical outcomes. PI3K pathway signaling inhibitors have been minimally investigated in Ph-like ALL. We hypothesized that targeted inhibition of PI3Kα, PI3Kδ, PI3K/mTOR, or target of rapamycin complex 1/2 (TORC1/TORC2) would decrease leukemia proliferation and abrogate aberrant kinase signaling and that combined PI3K pathway and JAK inhibition or PI3K pathway and SRC/ABL inhibition would have superior efficacy compared to inhibitor monotherapy. We treated 10 childhood ALL patient-derived xenograft models harboring various Ph-like genomic alterations with 4 discrete PI3K pathway protein inhibitors and observed marked leukemia reduction and in vivo signaling inhibition in all models. Treatment with dual PI3K/mTOR inhibitor gedatolisib resulted in near eradication of ALL in cytokine receptor-like factor 2 (CRLF2)/JAK-mutant models with mean 92.2% (range, 86.0%-99.4%) reduction vs vehicle controls (P < .0001) and in prolonged animal survival. Gedatolisib also inhibited ALL proliferation in ABL/platelet-derived growth factor receptor (PDGFR)-mutant models with mean 66.9% (range, 42.0%-87.6%) reduction vs vehicle (P < .0001). Combined gedatolisib and ruxolitinib treatment of CRLF2/JAK-mutant models more effectively inhibited ALL proliferation than either inhibitor alone (P < .001) and further enhanced survival. Similarly, superior efficacy of combined gedatolisib and dasatinib was observed in ABL/PDGFR-mutant models (P < .001). Overall, PI3K/mTOR inhibition potently decreased ALL burden in vivo; antileukemia activity was further enhanced with combination inhibitor therapy. Clinical trials testing combinations of kinase inhibitors in Ph-like ALL patients are indicated.
[Mh] MeSH terms primary: Antineoplastic Agents/pharmacology
Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
Protein Kinase Inhibitors/pharmacology
Signal Transduction/drug effects
[Mh] MeSH terms secundary: Animals
Cell Proliferation/drug effects
Humans
Janus Kinases/antagonists & inhibitors
Mice
Phosphatidylinositol 3-Kinases/antagonists & inhibitors
Proto-Oncogene Proteins c-abl/antagonists & inhibitors
Random Allocation
TOR Serine-Threonine Kinases/antagonists & inhibitors
Xenograft Model Antitumor Assays
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.10.2 (Janus Kinases); EC 2.7.10.2 (Proto-Oncogene Proteins c-abl)
[Em] Entry month:1708
[Cu] Class update date: 180112
[Lr] Last revision date:180112
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:161026
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-05-707653

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[PMID]: 28466386
[Au] Autor:Wang Z; Guo Y; Han W
[Ad] Address:Molecular & Immunological Department, Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
[Ti] Title:Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment.
[So] Source:Protein Cell;8(12):896-925, 2017 Dec.
[Is] ISSN:1674-8018
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:Chimeric antigen receptor (CAR) is a recombinant immunoreceptor combining an antibody-derived targeting fragment with signaling domains capable of activating cells, which endows T cells with the ability to recognize tumor-associated surface antigens independent of the expression of major histocompatibility complex (MHC) molecules. Recent early-phase clinical trials of CAR-modified T (CAR-T) cells for relapsed or refractory B cell malignancies have demonstrated promising results (that is, anti-CD19 CAR-T in B cell acute lymphoblastic leukemia (B-ALL)). Given this success, broadening the clinical experience of CAR-T cell therapy beyond hematological malignancies has been actively investigated. Here we discuss the basic design of CAR and review the clinical results from the studies of CAR-T cells in B cell leukemia and lymphoma, and several solid tumors. We additionally discuss the major challenges in the further development and strategies for increasing anti-tumor activity and safety, as well as for successful commercial translation.
[Mh] MeSH terms primary: Immunity, Cellular
Immunotherapy
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Receptors, Antigen, T-Cell/immunology
Recombinant Fusion Proteins/immunology
T-Lymphocytes
[Mh] MeSH terms secundary: Animals
Humans
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy
T-Lymphocytes/immunology
T-Lymphocytes/transplantation
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Nm] Name of substance:0 (Receptors, Antigen, T-Cell); 0 (Recombinant Fusion Proteins)
[Em] Entry month:1712
[Cu] Class update date: 171226
[Lr] Last revision date:171226
[Js] Journal subset:IM
[Da] Date of entry for processing:170504
[St] Status:MEDLINE
[do] DOI:10.1007/s13238-017-0400-z

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[PMID]: 29025600
[Au] Autor:Sadras T; Heatley SL; Kok CH; McClure BJ; Yeung D; Hughes TP; Sutton R; Ziegler DS; White DL
[Ad] Address:Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia.
[Ti] Title:A novel somatic JAK2 kinase-domain mutation in pediatric acute lymphoblastic leukemia with rapid on-treatment development of LOH.
[So] Source:Cancer Genet;216-217:86-90, 2017 Oct.
[Is] ISSN:2210-7762
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:We report a novel somatic mutation in the kinase domain of JAK2 (R938Q) in a high-risk pediatric case of B-cell acute lymphoblastic leukemia (ALL). The patient developed on-therapy relapse at 12 months, and interestingly, the JAK2 locus acquired loss of heterozygosity during treatment resulting in 100% mutation load. Furthermore, we show that primary ALL mononuclear cells harboring the JAK2 R938Q mutation display reduced sensitivity to the JAK1/2 ATP-competitive inhibitor ruxolitinib in vitro, compared to ALL cells that carry a more common JAK2 pseudokinase domain mutation. Our findings are in line with previous reports that demonstrate that mutations within the kinase domain of JAK2 are associated with resistance to type I JAK inhibitors. Importantly, given the recent inclusion of ruxolitinib in trial protocols for children with JAK pathway alterations, we predict that inter-patient genetic variability may result in suboptimal responses to JAK inhibitor therapy in a subset of cases. The need for alternate targeted and/or combination therapies for patients who display inherent or developed resistance to JAK inhibitor therapy will be warranted, and we propose that kinase-mutants less sensitive to type I JAK inhibitors may present a currently unexplored platform for investigation of improved therapies.
[Mh] MeSH terms primary: Janus Kinase 2/chemistry
Janus Kinase 2/genetics
Loss of Heterozygosity/genetics
Mutation/genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
[Mh] MeSH terms secundary: Base Sequence
Child
Female
Gene Rearrangement/genetics
Humans
Protein Domains
Recurrence
[Pt] Publication type:CASE REPORTS; JOURNAL ARTICLE
[Nm] Name of substance:EC 2.7.10.2 (JAK2 protein, human); EC 2.7.10.2 (Janus Kinase 2)
[Em] Entry month:1710
[Cu] Class update date: 171030
[Lr] Last revision date:171030
[Js] Journal subset:IM
[Da] Date of entry for processing:171014
[St] Status:MEDLINE


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