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T-cell acute lymphoblastic leukemia

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https://www.readbyqxmd.com/read/28922466/blinatumomab-pharmacodynamics-and-exposure-response-relationships-in-relapsed-refractory-acute-lymphoblastic-leukemia
#1
Min Zhu, Andrea Kratzer, Jessica Johnson, Chris Holland, Christian Brandl, Indrajeet Singh, Andreas Wolf, Sameer Doshi
We evaluated blinatumomab pharmacokinetics, pharmacodynamics (CD3+ T-cell, CD19+ B-cell, and cytokine levels), and their associations with efficacy or safety in relapsed/refractory acute lymphoblastic leukemia. Blinatumomab pharmacokinetics (continuous intravenous infusion) from a phase 2 study (n = 189; NCT01466179) were assessed noncompartmentally. Associations between steady-state concentration (Css ) and efficacy (complete remission [CR] or CR with partial hematologic recovery [CRh]) or safety (cytokine release syndrome [CRS] and neurologic events [NEs]) were evaluated with statistical models...
September 18, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921818/blinatumomab-activity-in-a-patient-with-down-syndrome-b-precursor-acute-lymphoblastic-leukemia
#2
Aman Wadhwa, Matthew A Kutny, Ana C Xavier
Persistent minimal residual disease (MRD) after consolidation may indicate chemotherapy insensitivity in B-precursor acute lymphoblastic leukemia (BP-ALL). Given the strong association of MRD and outcome in non-Down syndrome (non-DS) BP-ALL, it is likely that MRD levels are also of prognostic significance in DS BP-ALL. We report here the successful use of blinatumomab, a bispecific T-cell engager antibody construct, in a patient with DS BP-ALL and persistent MRD at the end of consolidation. Blinatumomab has been shown to have excellent results in patients with relapsed/refractory BP-ALL...
September 17, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28919785/biomarker-analysis-and-clinical-relevance-of-tk1-on-the-cell-membrane-of-burkitt-s-lymphoma-and-acute-lymphoblastic-leukemia
#3
Evita G Weagel, Wei Meng, Michelle H Townsend, Edwin J Velazquez, Rachel A Brog, Michael W Boyer, K Scott Weber, Richard A Robison, Kim L O'Neill
TK1 is an enzyme involved in DNA synthesis and repair. TK1 is usually found elevated in cancer patients' serum, which makes it a useful tumor proliferation biomarker that strongly correlates with cancer stage, metastatic capabilities, and recurrence risk. In this study, we show that TK1 is upregulated and localizes on the plasma membrane of Burkitt's lymphoma, acute promyelocytic leukemia, T cell leukemia, and acute lymphoblastic leukemia (ALL). Using flow cytometry, we confirmed that TK1 localizes on the surface of Raji, HL60, and Jurkat cell lines and on ALL clinical samples...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28917156/tgf%C3%AE-1-synergizes-with-flt3-ligand-to-induce-chemoresistant-quiescence-in-acute-lymphoblastic-leukemia-with-mll-gene-rearrangements
#4
M Tamai, Y Furuichi, S Kasai, N Ando, D Harama, K Goi, T Inukai, K Kagami, M Abe, H Ichikawa, K Sugita
Fms-like tyrosine kinase 3 (FLT3) is highly expressed in mixed-lineage leukemia (MLL) gene-rearranged acute lymphoblastic leukemia (MLL+ALL) with a dismal prognosis. We previously reported that FLT3 ligand (FL) stimulation induced cell cycle arrest in MLL+ALL cells leading to resistance against anti-leukemic agents. Given that FL stimulation enhanced transforming growth factor (TGF)β1 mRNA levels in MLL+ALL cells, we extensively examined the effect of TGFβ1 on the cell cycle progression and chemosensitivity in MLL+ALL cells, and found that TGFβ1 stimulation induced MLL+ALL cells into cell cycle arrest resistant to arabinosyl cytosine; its effect was markedly enhanced in synergy with FL...
September 13, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28914259/epigenetic-targeting-of-notch1-driven-transcription-using-the-hdaci-panobinostat-is-a-potential-therapy-against-t-cell-acute-lymphoblastic-leukemia
#5
M Waibel, S J Vervoort, I Y Kong, S Heinzel, K M Ramsbottom, B P Martin, E D Hawkins, R W Johnstone
Leukemia accepted article preview online, 15 September 2017. doi:10.1038/leu.2017.282.
September 15, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28905428/cost-effective-screening-of-dnmt3a-coding-sequence-identifies-somatic-mutation-in-pediatric-t-cell-acute-lymphoblastic-leukemia
#6
Bronisława Szarzyńska-Zawadzka, Maria Kosmalska, Łukasz Sędek, Alicja Sonsala, Magdalena Twardoch, Jerzy R Kowalczyk, Tomasz Szczepański, Michał Witt, Małgorzata Dawidowska
BACKGROUND AND OBJECTIVES: In pediatric T-cell acute lymphoblastic leukemia (T-ALL) risk assignment schemes preclude reliable prediction of outcome and thus new prognostic factors are needed. Mutations in DNMT3A are candidate prognostic and classification markers in adults with acute myeloid leukemia (AML) and T-ALL and thus were considered as candidates prognostic markers in pediatric T-ALL. PATIENTS AND METHODS: DNMT3A mutational status was investigated in 74 pediatric T-ALL samples collected at diagnosis...
September 14, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28887358/first-ever-car-t-cell-therapy-approved-in-u-s
#7
(no author information available yet)
The first chimeric antigen receptor T-cell therapy, tisagenlecleucel, received FDA approval for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia who haven't responded to standard therapy or who have relapsed at least twice.
September 8, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28887175/epigenetics-in-pediatric-acute-lymphoblastic-leukemia
#8
REVIEW
Jessica Nordlund, Ann-Christine Syvänen
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. ALL arises from the malignant transformation of progenitor B- and T-cells in the bone marrow into leukemic cells, but the mechanisms underlying this transformation are not well understood. Recent technical advances and decreasing costs of methods for high-throughput DNA sequencing and SNP genotyping have stimulated systematic studies of the epigenetic changes in leukemic cells from pediatric ALL patients. The results emerging from these studies are increasing our understanding of the epigenetic component of leukemogenesis and have demonstrated the potential of DNA methylation as a biomarker for lineage and subtype classification, prognostication, and disease progression in ALL...
September 5, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28884915/severe-mucha-habermann-like-ulceronecrotic-skin-disease-in-t-cell-acute-lymphoblastic-leukemia-responsive-to-basiliximab-and-stem-cell-transplant
#9
Lauren A V Orenstein, Carrie C Coughlin, Andrea T Flynn, Vinodh Pillai, Markus D Boos, Gerald B Wertheim, James R Treat, David T Teachey
A 5-year-old girl with T-cell acute lymphoblastic leukemia (T-ALL) developed a progressive eruption of crusted papules and ulcerative plaques involving 80% of her body surface area with histopathology consistent with febrile ulceronecrotic Mucha-Habermann disease (FUMHD), although multiple specimens also contained clonal leukemic cells. Her skin disease was refractory to many classic treatments for FUMHD, including methotrexate, and became so severe that concern about superinfection prevented intensification of chemotherapy for her malignancy...
September 2017: Pediatric Dermatology
https://www.readbyqxmd.com/read/28872614/aberrant-signaling-pathways-in-t-cell-acute-lymphoblastic-leukemia
#10
REVIEW
Deborah Bongiovanni, Valentina Saccomani, Erich Piovan
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth...
September 5, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28860956/diagnosis-of-lymphoid-malignancy-by-pcr-for-analysis-of-antigen-receptor-rearrangement-after-blood-transfusion-in-a-dog-with-acute-lymphocytic-leukemia
#11
Suhee Kim, Hyunwoo Kim, Soo-Hyeon Lee, Ilhan Cho, Seongwoo Kang, Junwoo Bae, Woosun Kim, Soomin Ahn, Jihye Choi, Sang-Ki Kim, Yoonjung Do, Jae Gyu Yoo, Jinho Park, DoHyeon Yu
Acute lymphocytic leukemia (ALL) is uncommon lymphoid malignancy in dogs, and its diagnosis is challenging. A 14-year-old spayed female mixed breed dog was transferred to a veterinary medical teaching hospital for an immediate blood transfusion. The dog showed lethargy, pale mucous membranes, and a weak femoral pulse. Complete blood count revealed non-regenerative anemia and severe leukopenia with thrombocytopenia. ALL was tentatively diagnosed based on the predominance of immature lymphoblasts on blood film examination...
August 2017: Immune Network
https://www.readbyqxmd.com/read/28852199/mutant-jak3-phosphoproteomic-profiling-predicts-synergism-between-jak3-inhibitors-and-mek-bcl2-inhibitors-for-the-treatment-of-t-cell-acute-lymphoblastic-leukemia
#12
S Degryse, C E de Bock, S Demeyer, I Govaerts, S Bornschein, D Verbeke, K Jacobs, S Binos, D A Skerrett-Byrne, H C Murray, N M Verrills, P Van Vlierberghe, J Cools, M D Dun
Mutations in the interleukin-7 receptor (IL7R) or the JAK3 kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here, we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib...
August 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28846072/mice-expressing-krasg12d-in-hematopoietic-multipotent-progenitor-cells-develop-neonatal-myeloid-leukemia
#13
Stefan P Tarnawsky, Rebecca J Chan, Mervin C Yoder
Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm that bears distinct characteristics associated with abnormal fetal development. JMML has been extensively modeled in mice expressing the oncogenic KrasG12D mutation. However, these models have struggled to recapitulate the defining features of JMML due to in utero lethality, nonhematopoietic expression, and the pervasive emergence of T cell acute lymphoblastic leukemia. Here, we have developed a model of JMML using mice that express KrasG12D in multipotent progenitor cells (Flt3Cre+ KrasG12D mice)...
August 28, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28843422/redirecting-t-cells-with-chimeric-antigen-receptor-car-for-the-treatment-of-childhood-acute-lymphoblastic-leukemia
#14
REVIEW
Andrea Biondi, Chiara F Magnani, Sarah Tettamanti, Giuseppe Gaipa, Ettore Biagi
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Nowadays the survival rate is around 85%. Nevertheless, an urgent clinical need is still represented by primary refractory and relapsed patients who do not significantly benefit from standard approaches, including chemo-radiotherapy and hematopoietic stem cell transplantation (HSCT). For this reason, immunotherapy has so far represented a challenging novel treatment opportunity, including, as the most validated therapeutic options, cancer vaccines, donor-lymphocyte infusions and tumor-specific immune effector cells...
August 23, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28841215/toll-like-receptor-2-costimulation-potentiates-the-antitumor-efficacy-of-car-t-cells
#15
Y Lai, J Weng, X Wei, L Qin, P Lai, R Zhao, Z Jiang, B Li, S Lin, S Wang, Q Wu, Z Tang, P Liu, D Pei, Y Yao, X Du, P Li
Chimeric antigen receptor (CAR) T-cell immunotherapies have shown unprecedented success in treating leukemia but limited clinical efficacy in solid tumors. Here, we generated 1928zT2 and m28zT2, targeting CD19 and mesothelin, respectively, by introducing the Toll/interleukin-1 receptor domain of Toll-like receptor 2 (TLR2) to 1928z and m28z. T cells expressing 1928zT2 or m28zT2 showed improved expansion, persistency and effector function against CD19(+) leukemia or mesothelin(+) solid tumors respectively in vitro and in vivo...
August 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28830639/t-cell-acute-lymphoblastic-leukemia-t-all-new-insights-into-the-cellular-origins-and-infiltration-mechanisms-common-and-unique-among-hematologic-malignancies
#16
REVIEW
Eduardo Vadillo, Elisa Dorantes-Acosta, Rosana Pelayo, Michael Schnoor
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% and 25% of total childhood and adult ALL cases, respectively. During T-ALL, patients are at risk of organ infiltration by leukemic T-cells. Infiltration is a major consequence of disease relapse and correlates with poor prognosis. Transendothelial migration of leukemic cells is required to exit the blood stream into target organs. While mechanisms of normal T-cell transmigration are well known, the mechanisms of leukemic T-cell extravasation remain elusive; but involvement of chemokines, integrins and Notch signaling play critical roles...
August 15, 2017: Blood Reviews
https://www.readbyqxmd.com/read/28827447/internal-deletion-of-bcor-reveals-a-tumor-suppressor-function-for-bcor-in-t-lymphocyte-malignancies
#17
Tomoyuki Tanaka, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Shiro Tara, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Sha Si, Ichiro Manabe, Masashi Sanada, Manabu Nakayama, Masayoshi Masuko, Hirohito Sone, Haruhiko Koseki, Atsushi Iwama
Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked BCOR gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains largely uncharacterized. We generated mice missing Bcor exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice (Bcor(ΔE4/y) ) compromised the repopulating capacity of hematopoietic stem cells, Bcor(ΔE4/y) thymocytes had augmented proliferative capacity in culture and showed a strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner...
August 21, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28827408/hematopoietic-stem-cell-involvement-in-bcr-abl1-positive-all-as-potential-mechanism-of-resistance-to-blinatumomab-therapy
#18
Inga Nagel, Marius Bartels, Johannes Duell, Hans-Heinrich Oberg, Sandra Ussat, Henrike Bruckmueller, Oliver Ottmann, Heike Pfeifer, Heiko Trautmann, Nicola Gökbuget, Almuth Caliebe, Dieter Kabelitz, Michael Kneba, Heinz-August Horst, Dieter Hoelzer, Max S Topp, Ingolf Cascorbi, Reiner Siebert, Monika Brüggemann
The bispecific T-cell engager blinatumomab targeting CD19 can induce complete remission in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, some patients ultimately relapse with loss of CD19-antigen on leukemic cells which has been established as a novel escape mechanism to CD19-specific immunotherapies. Here, we provide evidence that CD19-negative relapse after CD19-directed therapy in BCP-ALL may be due to selection of preexisting CD19-negative malignant progenitor cells...
August 21, 2017: Blood
https://www.readbyqxmd.com/read/28821272/novel-immunotherapies-for-adult-patients-with-b-lineage-acute-lymphoblastic-leukemia
#19
REVIEW
Guoqing Wei, Jiasheng Wang, He Huang, Yanmin Zhao
The past decade witnessed the rapid development of adult B-lineage acute lymphoblastic leukemia (ALL) treatment. Beyond the development of chemotherapy regimens, immunotherapy is starting a new era with unprecedented complete remission (CR) rate. Targeting B-lineage-specific surface markers such as CD19, CD20, CD22, or CD52, immunotherapy has been demonstrating promising clinical results. Among the immunotherapeutic methods, naked monoclonal antibodies (mAbs), antibody-drug conjugate (ADC), bispecific T cell engager (BiTE), and chimeric antigen receptor (CAR) T cells are the main types...
August 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28811744/cytogenetic-profile-and-flt3-gene-mutations-of-childhood-acute-lymphoblastic-leukemia
#20
Nawaf Alkhayat, Yasser Elborai, Omer Al Sharif, Mohammad Al Shahrani, Omar Alsuhaibani, Mohammed Awad, Hatem Elghezal, Inesse Ben-Abdallah Bouhajar, Mona Alfaraj, Eman Al Mussaed, Fahad Alabbas, Ghaleb Elyamany
BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent genetic aberrations. The identification of those abnormalities is clinically important because they are considered significant risk-stratifying markers. AIMS: There are insufficient data of cytogenetic profiles in Saudi Arabian patients with childhood ALL leukemia. We have examined a cohort of 110 cases of ALL to determine the cytogenetic profiles and prevalence of FLT3 mutations and analysis of the more frequently observed abnormalities and its correlations to other biologic factors and patient outcomes and to compare our results with previously published results...
2017: Clinical Medicine Insights. Oncology
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