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Leukemic stem cell

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https://www.readbyqxmd.com/read/29907810/asxl1-ezh2-mutations-promote-clonal-expansion-of-neoplastic-hsc-and-impair-erythropoiesis-in-pmf
#1
Ioanna Triviai, Silke Zeschke, Jan Rentel, Marios Spanakis, Theo Scherer, Razif Gabdoulline, Victoria Panagiota, Felicitas Thol, Michael Heuser, Carol Stocking, Nicolaus Kröger
Primary myelofibrosis (PMF) is a hematopoietic stem cell (HSC) disease, characterized by aberrant differentiation of all myeloid lineages and profound disruption of the bone marrow niche. PMF samples carry several mutations, but their cell origin and hierarchy in regulating the different waves of clonal and aberrant myeloproliferation from the prime HSC compartment is poorly understood. Genotyping of >2000 colonies from CD133+HSC and progenitors from PMF patients confirmed the complex genetic heterogeneity within the neoplastic population...
June 15, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29905026/chronic-myelogenous-leukemia-on-target
#2
Veronika Némethová, Filip Rázga
Chronic myelogenous leukemia (CML) is commonly treated with tyrosine kinase inhibitors (TKIs) that inhibit the pro-leukemic activity of the BCR-ABL1 oncoprotein. Despite the therapeutic progress mediated by TKI use, off-target effects, treatment-induced drug resistance, and the limited effect of these drugs on CML stem cells (SCs) are major drawbacks frequently resulting in insufficient or unsustainable treatment. Therefore, intense research efforts have focused on development of improved TKIs and alternative treatment strategies to eradicate CML SCs...
June 14, 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29901649/nephrogenic-diabetes-insipidus-in-initial-stage-of-acute-lymphoblastic-leukemia-and-relapse-after-haploidentical-hematopoietic-stem-cell-transplantation-a-case-report
#3
Dezhi Li, Qian Liu, Zhifang Feng, Qi Zhang, Saran Feng
RATIONALE: Nephrogenic diabetes insipidus (NDI) rarely presents in the initial stage of acute lymphoblastic leukemia (ALL) and relapse due to renal infiltration is also rare. PATIENT CONCERNS: A 19-year-old man presented with weakness, polydipsia, and polyuria for 1 month. DIAGNOSES: NDI was diagnosed with insignificant response to a water deprivation test after stimulation with vasopressin injection. Bone marrow examination combined with immunophenotypic analysis, cerebrospinal cytology, and abdominal ultrasonography confirmed the diagnoses of precursor B cell ALL with renal infiltration...
June 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29900128/residual-peripheral-blood-cd26-leukemic-stem-cells-in-chronic-myeloid-leukemia-patients-during-tki-therapy-and-during-treatment-free-remission
#4
Monica Bocchia, Anna Sicuranza, Elisabetta Abruzzese, Alessandra Iurlo, Santina Sirianni, Antonella Gozzini, Sara Galimberti, Lara Aprile, Bruno Martino, Patrizia Pregno, Federica Sorà, Giulia Alunni, Carmen Fava, Fausto Castagnetti, Luca Puccetti, Massimo Breccia, Daniele Cattaneo, Marzia Defina, Olga Mulas, Claudia Baratè, Giovanni Caocci, Simona Sica, Alessandro Gozzetti, Luigiana Luciano, Monica Crugnola, Mario Annunziata, Mario Tiribelli, Paola Pacelli, Ilaria Ferrigno, Emilio Usala, Nicola Sgherza, Gianantonio Rosti, Alberto Bosi, Donatella Raspadori
Chronic myeloid leukemia (CML) patients in sustained "deep molecular response" may stop TKI treatment without disease recurrence; however, half of them lose molecular response shortly after TKI withdrawing. Well-defined eligibility criteria to predict a safe discontinuation up-front are still missing. Relapse is probably due to residual quiescent TKI-resistant leukemic stem cells (LSCs) supposedly transcriptionally low/silent and not easily detectable by BCR-ABL1 qRT-PCR. Bone marrow Ph+ CML CD34+ /CD38- LSCs were found to specifically co-express CD26 (dipeptidylpeptidase-IV)...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29895969/inhibition-of-maternal-embryonic-leucine-zipper-kinase-with-otssp167-displays-potent-anti-leukemic-effects-in-chronic-lymphocytic-leukemia
#5
Ya Zhang, Xiangxiang Zhou, Ying Li, Yangyang Xu, Kang Lu, Peipei Li, Xin Wang
TP53 pathway defects contributed to therapy resistance and adverse clinical outcome in chronic lymphocytic leukemia (CLL), which represents an unmet clinical need with few therapeutic options. Maternal embryonic leucine zipper kinase (MELK) is a novel oncogene, which plays crucial roles in mitotic progression and stem cell maintenance. OTSSP167, an orally administrated inhibitor targeting MELK, is currently in a phase I/II clinical trial in patients with advanced breast cancer and acute myeloid leukemia. Yet, no investigation has been elucidated to date regarding the oncogenic role of MELK and effects of OTSSP167 in chronic lymphocytic leukemia (CLL)...
June 12, 2018: Oncogene
https://www.readbyqxmd.com/read/29895435/extramedullary-relapse-and-discordant-cd19-expression-between-bone-marrow-and-extramedullary-sites-in-relapsed-acute-lymphoblastic-leukemia-after-blinatumomab-treatment
#6
Christos Demosthenous, Chrysavgi Lalayanni, Michalis Iskas, Vassiliki Douka, Nikoleta Pastelli, Achilles Anagnostopoulos
Blinatumomab, a bispecific T-cell engager antibody construct targeting CD19, has been shown to improve the outcome in patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia. Treatment with blinatumomab demonstrated significant survival benefit over chemotherapy, supporting its use as a bridge therapy to allogeneic hematopoietic stem cell transplantation. Unfortunately, following initial response, approximately 50% of responding patients eventually relapse. At the time of failure, the majority of patients have CD19-positive blasts, yet a concerning number of CD19-negative relapses has been reported...
May 7, 2018: Current Problems in Cancer
https://www.readbyqxmd.com/read/29884901/preclinical-evaluation-of-the-selective-small-molecule-uba1-inhibitor-tak-243-in-acute-myeloid-leukemia
#7
Samir H Barghout, Parasvi S Patel, Xiaoming Wang, G Wei Xu, Simon Kavanagh, Ondrej Halgas, Sara F Zarabi, Marcela Gronda, Rose Hurren, Danny V Jeyaraju, Neil MacLean, Shawn Brennan, Marc L Hyer, Allison Berger, Tary Traore, Michael Milhollen, Adam C Smith, Mark D Minden, Emil F Pai, Razq Hakem, Aaron D Schimmer
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy for which new therapeutic approaches are required. One such potential therapeutic strategy is to target the ubiquitin-like modifier-activating enzyme 1 (UBA1), the initiating enzyme in the ubiquitylation cascade in which proteins are tagged with ubiquitin moieties to regulate their degradation or function. Here, we evaluated TAK-243, a first-in-class UBA1 inhibitor, in preclinical models of AML. In AML cell lines and primary AML samples, TAK-243 induced cell death and inhibited clonogenic growth...
June 8, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29879518/chromosomal-aberrations-and-survival-after-unrelated-donor-hematopoietic-stem-cell-transplant-in-patients-with-fanconi-anemia
#8
Youjin Wang, Weiyin Zhou, Blanche P Alter, Tao Wang, Stephen R Spellman, Michael Haagenson, Meredith Yeager, Stephanie J Lee, Stephen J Chanock, Sharon A Savage, Shahinaz M Gadalla
Studies of chromosomal aberrations in blood or bone marrow of patients with Fanconi anemia (FA) have focused on their associations with leukemic transformation. The role of such abnormalities on outcomes after hematopoietic cell transplantation (HCT) is unclear. We used genome-wide single nucleotide polymorphism (SNP) arrays to identify chromosomal aberrations in pre-HCT blood samples from 73 patients with FA who received unrelated donor HCT for severe aplastic anemia between 1991-2007. Outcome data and blood samples were available through the Center for International Blood and Marrow Transplant Research...
June 4, 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29878897/prdm16-isoforms-differentially-regulate-normal-and-leukemic-hematopoiesis-and-inflammatory-gene-signature
#9
David J Corrigan, Larry L Luchsinger, Mariana Justino de Almeida, Linda J Williams, Alexandros Strikoudis, Hans-Willem Snoeck
PRDM16 is a transcriptional co-regulator involved in translocations in acute myeloblastic leukemia (AML), myelodysplastic syndromes and T acute lymphoblastic leukemia that is highly expressed in and required for the maintenance of hematopoietic stem cells (HSCs), and can be aberrantly expressed in AML. Prdm16 is expressed as full-length (fPrdm16) and short (sPrdm16) isoforms, the latter lacking the N-terminal PR-domain. The role of both isoforms in normal and malignant hematopoiesis is unclear. We show here that fPrdm16 was critical for HSC maintenance, induced multiple genes involved in GTPase signaling and repressed inflammation, while sPrdm16 supported B-cell development biased towards marginal zone B-cells and induced an inflammatory signature...
June 7, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29878489/chronic-myelomonocytic-leukemia-2018-update-on-diagnosis-risk-stratification-and-management
#10
Mrinal M Patnaik, Ayalew Tefferi
DISEASE OVERVIEW: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (∼15%-20% over 3-5 years). DIAGNOSIS: Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 109 /L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ∼ 30% of patients, while >90% have gene mutations...
June 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29877252/-functional-role-of-dnmt3a-mutation-in-acute-myeloid-leukemia
#11
Junji Koya, Mineo Kurokawa
A current broad spectrum of genomic studies on acute myeloid leukemia (AML) has demonstrated that a gene encoding for DNA methyltransferase, specifically DNA methyltransferase 3 alpha (DNMT3A) is frequently mutated. However, DNMT3A variants are present in elderly healthy individuals and patients with AML in complete remission, which suggests that DNMT3A mutations may contribute to pre-leukemic clonal hematopoiesis. Although DNMT3A mutation has been thought to play a pivotal role in AML pathogenesis through the loss of DNA methylation functionality, other potential disease-related mechanisms are poorly understood...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/29868474/therapeutic-antibodies-for-myeloid-neoplasms-current-developments-and-future-directions
#12
REVIEW
Christian M Schürch
Therapeutic monoclonal antibodies (mAbs) such as antibody-drug conjugates, ligand-receptor antagonists, immune checkpoint inhibitors and bispecific T cell engagers have shown impressive efficacy in the treatment of multiple human cancers. Numerous therapeutic mAbs that have been developed for myeloid neoplasms, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are currently investigated in clinical trials. Because AML and MDS originate from malignantly transformed hematopoietic stem/progenitor cells-the so-called leukemic stem cells (LSCs) that are highly resistant to most standard drugs-these malignancies frequently relapse and have a high disease-specific mortality...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29849981/effects-of-hypoxia-on-biology-of-human-leukemia-t-cell-line-molt-4-cells-co-cultured-with-bone-marrow-mesenchymal-stem-cells
#13
Sina Baharaghdam, Mehdi Yousefi, Aliakbar Movasaghpour, Saeed Solali, Mehdi Talebi, Milad Ahani-Nahayati, Hamid Lotfimehr, Karim Shamsasanjan
Background: One of the most significant problems in the treatment of leukemia is the expansion of resistance to chemotherapeutic agents. Therefore, assessing the drug resistance and especially the drug resistance genes of leukemic cells is important in any treatment. The impact of Mesenchymal Stem Cells (MSCs) and hypoxic condition have been observed in the biological performance of majority of leukemic cells. Methods: MOLT-4 cells were co-cultured with MSCs in the hypoxic condition induced by Cobalt Chloride (CoCl2 ) for 6 and 24 hr ...
April 2018: Avicenna Journal of Medical Biotechnology
https://www.readbyqxmd.com/read/29845257/montelukast-a-cysteinyl-leukotriene-receptor-antagonist-inhibits-the-growth-of-chronic-myeloid-leukemia-cells-through-apoptosis
#14
Ana Zovko, Elham Yektaei-Karin, Daniel Salamon, Anders Nilsson, Jonas Wallvik, Leif Stenke
The clinical outcome for patients with chronic myeloid leukemia (CML) has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs). However, their curative potential appears limited, probably as a consequence of TKI-resistant leukemic stem cells (LSCs) that persist as a result of aberrant pathways independent of the well-established oncoprotein Bcr-Abl. One such pathway involves signaling through leukotrienes (LTs), bioactive compounds that have been suggested to play a role in several other malignancies...
May 25, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29844011/usp22-deficiency-leads-to-myeloid-leukemia-upon-oncogenic-kras-activation-through-a-pu-1-dependent-mechanism
#15
Johanna Melo-Cardenas, Yuanming Xu, Juncheng Wei, Can Tan, Sinyi Kong, Beixue Gao, Elena Montauti, Gina Kirsammer, Jonathan D Licht, Jindan Yu, Peng Ji, John D Crispino, Deyu Fang
Ras mutations are commonly observed in Juvenile Myelomonocytic Leukemia (JMML) and Chronic Myelomonocytic Leukemia (CMML). JMML and CMML transform into Acute Myeloid Leukemia (AML) in about 10% and 50% of patients respectively. However, how additional events cooperate with Ras to promote this transformation are largely unknown. We show that absence of the Ubiquitin-Specific-peptidase 22 (USP22), a component of the SAGA chromatin-remodeling complex linked to cancer progression, unexpectedly promotes AML transformation in mice expressing oncogenic KrasG12D/+ USP22 deficiency in KrasG12D/+ mice resulted in shorter survival compared to control mice...
May 29, 2018: Blood
https://www.readbyqxmd.com/read/29784639/tyrosine-kinase-inhibitor-induced-defects-in-dna-repair-sensitize-flt3-itd-positive-leukemia-cells-to-parp1-inhibitors
#16
Silvia Maifrede, Margaret Nieborowska-Skorska, Katherine Sullivan, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Bac Viet Le, Martyna Solecka, Zhaorui Lian, Elizaveta A Belyaeva, Alina Nersesyan, Marcin M Machnicki, Monika Toma, Nicolas Chatain, Malgorzata Rydzanicz, Huaqing Zhao, Jaroslav Jelinek, Katarzyna Piwocka, Tomasz Sliwinski, Tomasz Stoklosa, Rafal Ploski, Thomas Fischer, Stephen M Sykes, Steffen Koschmieder, Lars Bullinger, Peter Valent, Mariusz Wasik, Jian Huang, Tomasz Skorski
Mutations in the FMS-like tyrosine-kinase 3 (FLT3) such as internal tandem duplications (ITD) can be found in up to 23% of patients with acute myeloid leukemia (AML) and confer a poor prognosis. Current treatment options for FLT3(ITD)-positive AMLs include genotoxic therapy and FLT3 inhibitors (FLT3i), which are rarely curative. PARP1 inhibitors (PARP1i) have been successfully applied to induce synthetic lethality in tumors harboring BRCA1/2 mutations and displaying homologous recombination (HR) deficiency...
May 21, 2018: Blood
https://www.readbyqxmd.com/read/29781563/associations-between-neutrophil-recovery-time-infections-and-relapse-in-pediatric-acute-myeloid-leukemia
#17
Ditte J A Løhmann, Peter H Asdahl, Jonas Abrahamsson, Shau-Yin Ha, Ólafur G Jónsson, Gertjan J L Kaspers, Minna Koskenvuo, Birgitte Lausen, Barbara De Moerloose, Josefine Palle, Bernward Zeller, Henrik Hasle
BACKGROUND: Children with acute myeloid leukemia (AML) treated similarly show different toxicity and leukemic responses. We investigated associations between neutrophil recovery time after the first induction course, infection and relapse in children treated according to NOPHO-AML 2004 and DB AML-01. PROCEDURE: Newly diagnosed patients with AML with bone marrow blast <5% between day 15 after the start of the treatment and the start of second induction course, and in complete remission after the second induction course were included (n = 279)...
May 21, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29780592/preleukemic-and-second-hit-mutational-events-in-an-acute-myeloid-leukemia-patient-with-a-novel-germline-runx1-mutation
#18
Isaac Ks Ng, Joanne Lee, Christopher Ng, Bustamin Kosmo, Lily Chiu, Elaine Seah, Michelle Meng Huang Mok, Karen Tan, Motomi Osato, Wee-Joo Chng, Benedict Yan, Lip Kun Tan
Background: Germline mutations in the RUNX1 transcription factor give rise to a rare autosomal dominant genetic condition classified under the entity: Familial Platelet Disorders with predisposition to Acute Myeloid Leukaemia (FPD/AML). While several studies have identified a myriad of germline RUNX1 mutations implicated in this disorder, second-hit mutational events are necessary for patients with hereditary thrombocytopenia to develop full-blown AML. The molecular picture behind this process remains unclear...
2018: Biomarker Research
https://www.readbyqxmd.com/read/29774100/differential-proteomic-profile-of-leukemic-cd34-progenitor-cells-from-chronic-myeloid-leukemia-patients
#19
Maria Rosaria Ricciardi, Valentina Salvestrini, Roberto Licchetta, Simone Mirabilii, Mattia Forcato, Gabriele Gugliotta, Simona Salati, Fausto Castagnetti, Gianantonio Rosti, Massimo Breccia, Giuliana Alimena, Rossella Manfredini, Silvio Bicciato, Roberto Massimo Lemoli, Agostino Tafuri
Chronic Myeloid Leukemia (CML) is a stem cell disease sustained by a rare population of quiescent cells which are to some extent resistant to tyrosine kinase inhibitors (TKIs). BCR-ABL oncogene activates multiple cross-talking signal transduction pathways (STP), such as RAS/MEK/ERK, PI3K/Akt, Wnt and STAT5, contributing to abnormal proliferation of clonal cells. From this perspective, the aim of this study was to analyze the expression and activation profile of STP involved in the mechanisms of cell proliferation/quiescence and survival of the progenitor CD34+ cells from chronic phase (CP) CML...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29773602/clofarabine-high-dose-cytarabine-and-liposomal-daunorubicin-in-pediatric-relapsed-refractory-acute-myeloid-leukemia-a-phase-ib-study
#20
Natasha K A van Eijkelenburg, Mareike Rasche, Essam Ghazaly, Michael N Dworzak, Thomas Klingebiel, Claudia Rossig, Guy Leverger, Jan Stary, Eveline S J M de Bont, Dana A Chitu, Yves Bertrand, Benoit Brethon, Brigitte Strahm, Inge M van der Sluis, Gertjan J L Kaspers, Dirk Reinhardt, C Michel Zwaan
Survival in children with relapsed/refractory acute myeloid leukemia is unsatisfactory. Treatment consists of one course fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase 2 dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose-levels of clofarabine (20-40mg/m2/day x5days) and liposomal daunorubicin (40-0mg/m2/day) were administered with cytarabine (2g/m2/day x5days)...
May 17, 2018: Haematologica
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