keyword
https://read.qxmd.com/read/38525233/cytokine-secretion-in-stem-cells-of-cattle-infected-with-bovine-leukaemia-virus
#1
JOURNAL ARTICLE
Maria Szczotka, Jacek Kuźmak
INTRODUCTION: Bovine leukaemia virus (BLV) is a Deltaretrovirus responsible for enzootic bovine leukosis, the most common neoplastic disease of cattle. It deregulates the immune system, favouring secondary infections and changes in the blood and lymphatic tissues. Blood homeostasis depends on functional haematopoietic stem cells (HSCs). Bone marrow is populated by these cells, which express CD34+ and CD35+ surface antigens and produce and release cytokines involved in the maintenance of haematopoiesis...
March 2024: Journal of Veterinary Research
https://read.qxmd.com/read/38461169/cannabinoids-induce-cell-death-in-leukaemic-cells-through-parthanatos-and-parp-related-metabolic-disruptions
#2
JOURNAL ARTICLE
M Medrano, M Contreras, T Caballero-Velázquez, L Martínez, J A Bejarano-García, R Calderón-Ruiz, C B García-Calderón, I V Rosado, J A Pérez-Simón
BACKGROUND: Several studies have described a potential anti-tumour effect of cannabinoids (CNB). CNB receptor 2 (CB2) is mostly present in hematopoietic stem cells (HSC). The present study evaluates the anti-leukaemic effect of CNB. METHODS: Cell lines and primary cells from acute myeloid leukaemia (AML) patients were used and the effect of the CNB derivative WIN-55 was evaluated in vitro, ex vivo and in vivo. RESULTS: We demonstrate a potent antileukemic effect of WIN-55 which is abolished with CB antagonists...
March 9, 2024: British Journal of Cancer
https://read.qxmd.com/read/38459168/myelodysplastic-neoplasms-dissected-into-indolent-leukaemic-and-unfavourable-subtypes-by-computational-clustering-of-haematopoietic-stem-and-progenitor-cells
#3
JOURNAL ARTICLE
Margot F van Spronsen, Sofie Van Gassen, Carolien Duetz, Theresia M Westers, Yvan Saeys, Arjan A van de Loosdrecht
Myelodysplastic neoplasms (MDS) encompass haematological malignancies, which are characterised by dysplasia, ineffective haematopoiesis and the risk of progression towards acute myeloid leukaemia (AML). Myelodysplastic neoplasms are notorious for their heterogeneity: clinical outcomes range from a near-normal life expectancy to leukaemic transformation or premature death due to cytopenia. The Molecular International Prognostic Scoring System made progress in the dissection of MDS by clinical outcomes. To contribute to the risk stratification of MDS by immunophenotypic profiles, this study performed computational clustering of flow cytometry data of CD34+ cells in 67 MDS, 67 AML patients and 49 controls...
March 8, 2024: Leukemia
https://read.qxmd.com/read/38456256/immunophenotypic-characterization-of-leukemic-stem-cells-in-acute-myeloid-leukemia-using-single-tube-10-colour-panel-by-multiparametric-flow-cytometry-deciphering-the-spectrum-complexity-and-immunophenotypic-heterogeneity
#4
JOURNAL ARTICLE
Nupur Das, Devasis Panda, Smeeta Gajendra, Ritu Gupta, Deepshi Thakral, Gurvinder Kaur, Aafreen Khan, Vivek Kumar Singh, Arushi Vemprala, Sameer Bakhshi, Rachna Seth, Ranjit Kumar Sahoo, Atul Sharma, Sandeep Rai, Vijay K Prajapati, Saroj Singh
INTRODUCTION: Despite extensive research, comprehensive characterization of leukaemic stem cells (LSC) and information on their immunophenotypic differences from normal haematopoietic stem cells (HSC) is lacking. Herein, we attempted to unravel the immunophenotypic (IPT) characteristics and heterogeneity of LSC using multiparametric flow cytometry (MFC) and single-cell sequencing. MATERIALS AND METHODS: Bone marrow aspirate samples from patients with acute myeloid leukaemia (AML) were evaluated using MFC at diagnostic and post induction time points using a single tube-10-colour-panel containing LSC-associated antibodies CD123, CD45RA, CD44, CD33 and COMPOSITE (CLL-1, TIM-3, CD25, CD11b, CD22, CD7, CD56) with backbone markers that is, CD45, CD34, CD38, CD117, sCD3...
March 8, 2024: International Journal of Laboratory Hematology
https://read.qxmd.com/read/38431691/inhibition-of-mitochondrial-folate-metabolism-drives-differentiation-through-mtorc1-mediated-purine-sensing
#5
JOURNAL ARTICLE
Martha M Zarou, Kevin M Rattigan, Daniele Sarnello, Engy Shokry, Amy Dawson, Angela Ianniciello, Karen Dunn, Mhairi Copland, David Sumpton, Alexei Vazquez, G Vignir Helgason
Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells...
March 2, 2024: Nature Communications
https://read.qxmd.com/read/38246924/activating-p53-abolishes-self-renewal-of-quiescent-leukaemic-stem-cells-in-residual-cml-disease
#6
JOURNAL ARTICLE
Mary T Scott, Wei Liu, Rebecca Mitchell, Cassie J Clarke, Ross Kinstrie, Felix Warren, Hassan Almasoudi, Thomas Stevens, Karen Dunn, John Pritchard, Mark E Drotar, Alison M Michie, Heather G Jørgensen, Brian Higgins, Mhairi Copland, David Vetrie
Whilst it is recognised that targeting self-renewal is an effective way to functionally impair the quiescent leukaemic stem cells (LSC) that persist as residual disease in chronic myeloid leukaemia (CML), developing therapeutic strategies to achieve this have proved challenging. We demonstrate that the regulatory programmes of quiescent LSC in chronic phase CML are similar to that of embryonic stem cells, pointing to a role for wild type p53 in LSC self-renewal. In support of this, increasing p53 activity in primitive CML cells using an MDM2 inhibitor in combination with a tyrosine kinase inhibitor resulted in reduced CFC outputs and engraftment potential, followed by loss of multilineage priming potential and LSC exhaustion when combination treatment was discontinued...
January 22, 2024: Nature Communications
https://read.qxmd.com/read/38083865/tp53-variant-allele-frequency-and-therapy-related-setting-independently-predict-survival-in-myelodysplastic-syndromes-with-del-5q
#7
JOURNAL ARTICLE
Ayalew Tefferi, Farah Fleti, Onyee Chan, Najla H Al Ali, Aref Al-Kali, Kebede H Begna, James M Foran, Talha Badar, Nandita Khera, Mithun Shah, Devendra Hiwase, Eric Padron, David A Sallman, Animesh Pardanani, Daniel A Arber, Attilio Orazi, Kaaren K Reichard, Rong He, Rhett P Ketterling, Naseema Gangat, Rami Komrokji
Among 210 patients with myelodysplastic syndromes (MDSs) with del(5q), molecular information was available at diagnosis or at least 3 months before leukaemic transformation in 146 cases. Multivariate analysis identified therapy-related setting (p = 0.02; HR 2.3) and TP53 variant allele frequency (VAF) ≥22% (p < 0.01; HR 2.8), but not SF3B1 mutation (p = 0.65), as independent risk factors for survival. Median survival was 11.7 versus 4 years (5/10-year survival 73%/52% vs...
December 11, 2023: British Journal of Haematology
https://read.qxmd.com/read/38065203/sabatolimab-plus-hypomethylating-agents-in-previously-untreated-patients-with-higher-risk-myelodysplastic-syndromes-stimulus-mds1-a-randomised-double-blind-placebo-controlled-phase-2-trial
#8
JOURNAL ARTICLE
Amer M Zeidan, Kiyoshi Ando, Odile Rauzy, Mehmet Turgut, Ming-Chung Wang, Roberto Cairoli, Hsin-An Hou, Yok-Lam Kwong, Montserrat Arnan, Stef Meers, Vinod Pullarkat, Valeria Santini, Kamel Malek, Flavia Kiertsman, Julie Niolat, Pedro Marques Ramos, Hans D Menssen, Pierre Fenaux, Yasushi Miyazaki, Uwe Platzbecker
BACKGROUND: Sabatolimab is an immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), an immuno-myeloid regulator expressed on immune cells and leukaemic stem cells. In this trial, we compared the efficacy and safety of sabatolimab plus hypomethylating agent with placebo plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes. METHODS: STIMULUS-MDS1 was a multicentre, randomised, double-blind, placebo-controlled, phase 2 study done at 54 investigational sites in 17 countries...
December 5, 2023: Lancet Haematology
https://read.qxmd.com/read/38031192/overcoming-bcr-abl1-dependent-and-independent-survival-mechanisms-in-chronic-myeloid-leukaemia-using-a-multi-kinase-targeting-approach
#9
JOURNAL ARTICLE
Caroline Busch, Theresa Mulholland, Michele Zagnoni, Matthew Dalby, Catherine Berry, Helen Wheadon
BACKGROUND: Despite improved patient outcome using tyrosine kinase inhibitors (TKIs), chronic myeloid leukaemia (CML) patients require life-long treatment due to leukaemic stem cell (LSC) persistence. LSCs reside in the bone marrow (BM) niche, which they modify to their advantage. The BM provides oncogene-independent signals to aid LSC cell survival and quiescence. The bone-morphogenetic pathway (BMP) is one pathway identified to be highly deregulated in CML, with high levels of BMP ligands detected in the BM, accompanied by CML stem and progenitor cells overexpressing BMP type 1 receptors- activin-like kinases (ALKs), especially in TKI resistant patients...
November 29, 2023: Cell Communication and Signaling: CCS
https://read.qxmd.com/read/37818364/spatial-proteomics-identifies-a-spectrum-of-immune-dysregulation-in-acquired-bone-marrow-failure-syndromes
#10
JOURNAL ARTICLE
Rachel M Koldej, Ashvind Prabahran, Chin Wee Tan, Mandy Ludford-Menting, Huw Morgan, Nicholas Holzwart, Melissa J Davis, David S Ritchie
Poor graft function (PGF), manifested by multilineage cytopenias and complete donor chimerism post-allogeneic stem cell transplantation (alloSCT), and acquired aplastic anaemia (AA) are immune-mediated acquired bone marrow (BM) failure syndromes with a similar clinical presentation. In this study, we used spatial proteomics to compare the immunobiology of the BM microenvironment and identify common mechanisms of immune dysregulation under these conditions. Archival BM trephines from patients exhibited downregulation of the immunoregulatory protein VISTA and the M2 macrophage marker and suppressor of T-cell activation ARG1 with increased expression of the immune checkpoint B7-H3 compared to normal controls...
2023: Frontiers in Immunology
https://read.qxmd.com/read/37802982/distinct-and-targetable-role-of-calcium-sensing-receptor-in-leukaemia
#11
JOURNAL ARTICLE
Raquel S Pereira, Rahul Kumar, Alessia Cais, Lara Paulini, Alisa Kahler, Jimena Bravo, Valentina R Minciacchi, Theresa Krack, Eric Kowarz, Costanza Zanetti, Parimala Sonika Godavarthy, Fabian Hoeller, Pablo Llavona, Tabea Stark, Georg Tascher, Daniel Nowak, Eshwar Meduri, Brian J P Huntly, Christian Münch, Francesco Pampaloni, Rolf Marschalek, Daniela S Krause
Haematopoietic stem cells (HSC) reside in the bone marrow microenvironment (BMM), where they respond to extracellular calcium [eCa2+ ] via the G-protein coupled calcium-sensing receptor (CaSR). Here we show that a calcium gradient exists in this BMM, and that [eCa2+ ] and response to [eCa2+ ] differ between leukaemias. CaSR influences the location of MLL-AF9+ acute myeloid leukaemia (AML) cells within this niche and differentially impacts MLL-AF9+ AML versus BCR-ABL1+ leukaemias. Deficiency of CaSR reduces AML leukaemic stem cells (LSC) 6...
October 6, 2023: Nature Communications
https://read.qxmd.com/read/37591854/pyruvate-anaplerosis-is-a-targetable-vulnerability-in-persistent-leukaemic-stem-cells
#12
JOURNAL ARTICLE
Kevin M Rattigan, Zuzana Brabcova, Daniele Sarnello, Martha M Zarou, Kiron Roy, Ryan Kwan, Lucie de Beauchamp, Amy Dawson, Angela Ianniciello, Ahmed Khalaf, Eric R Kalkman, Mary T Scott, Karen Dunn, David Sumpton, Alison M Michie, Mhairi Copland, Saverio Tardito, Eyal Gottlieb, G Vignir Helgason
Deregulated oxidative metabolism is a hallmark of leukaemia. While tyrosine kinase inhibitors (TKIs) such as imatinib have increased survival of chronic myeloid leukaemia (CML) patients, they fail to eradicate disease-initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays, we generate multi-omics datasets that offer unique insight into metabolic adaptation and nutrient fate in patient-derived CML LSCs...
August 17, 2023: Nature Communications
https://read.qxmd.com/read/37489735/arginine-dependency-is-a-therapeutically-exploitable-vulnerability-in-chronic-myeloid-leukaemic-stem-cells
#13
JOURNAL ARTICLE
Kevin M Rattigan, Martha M Zarou, Zuzana Brabcova, Bodhayan Prasad, Désirée Zerbst, Daniele Sarnello, Eric R Kalkman, Angela Ianniciello, Mary T Scott, Karen Dunn, Engy Shokry, David Sumpton, Mhairi Copland, Saverio Tardito, Johan Vande Voorde, Francis Mussai, Paul Cheng, G Vignir Helgason
To fuel accelerated proliferation, leukaemic cells undergo metabolic deregulation, which can result in specific nutrient dependencies. Here, we perform an amino acid drop-out screen and apply pre-clinical models of chronic phase chronic myeloid leukaemia (CML) to identify arginine as a nutrient essential for primary human CML cells. Analysis of the Microarray Innovations in Leukaemia (MILE) dataset uncovers reduced ASS1 levels in CML compared to most other leukaemia types. Stable isotope tracing reveals repressed activity of all urea cycle enzymes in patient-derived CML CD34+ cells, rendering them arginine auxotrophic...
October 9, 2023: EMBO Reports
https://read.qxmd.com/read/37193639/hax1-related-congenital-neutropenia-long-term-observation-in-paediatric-and-adult-patients-enrolled-in-the-european-branch-of-the-severe-chronic-neutropenia-international-registry-scnir
#14
JOURNAL ARTICLE
Denys Pogozhykh, Deniz Yilmaz Karapinar, Maksim Klimiankou, Natali Gerschmann, Georg Ebetsberger-Dachs, Jan Palmblad, Göran Carlsson, Tania Masmas, Sally Kinsey, Marije Bartels, Sabine Mellor-Heineke, Karl Welte, Julia Skokowa, Cornelia Zeidler
HAX1-related congenital neutropenia (HAX1-CN) is a rare autosomal recessive disorder caused by pathogenic variants in the HAX1 gene. HAX1-CN patients suffer from bone marrow failure as assessed by a maturation arrest of the myelopoiesis revealing persistent severe neutropenia from birth. The disorder is strongly associated with severe bacterial infections and a high risk of developing myelodysplastic syndrome or acute myeloid leukaemia. This study aimed to describe the long-term course of the disease, the treatment, outcome and quality of life in patients with homozygous HAX1 mutations reported to the European branch of the Severe Chronic Neutropenia International Registry...
July 2023: British Journal of Haematology
https://read.qxmd.com/read/37119247/enpp4-and-hoxa3-as-potential-leukaemia-stem-cell-markers-in-acute-myeloid-leukaemia
#15
JOURNAL ARTICLE
A Mohd Amin, N Panneerselvan, S Md Noor, N Mohtaruddin, J Sathar, W S Norbaya, R Osman, L H Kee, W H Mohd Yaakub, S K Cheong, M Abdullah
INTRODUCTION: Acute myeloid leukaemia (AML) is a heterogeneous malignant disease with a high degree of treatment failure using chemotherapy. Leukaemia stem cells (LSCs) are CD34+CD38- early progenitors associated with poor prognosis in AML. A unique LSC phenotype that excludes rare normal haematopoietic stem cells (HSC) is still elusive. This study aimed to determine expression of selected potential LSC markers in normal and leukaemic myeloid cells and correlate prognosis in AML patients...
April 2023: Malaysian Journal of Pathology
https://read.qxmd.com/read/36951259/a-mirna-signature-related-to-stemness-identifies-high-risk-patients-in-paediatric-acute-myeloid-leukaemia
#16
JOURNAL ARTICLE
Elena Esperanza-Cebollada, Soledad Gómez-González, Sara Perez-Jaume, Nerea Vega-García, Clara Vicente-Garcés, Mercè Richarte-Franqués, Susana Rives, Albert Català, Montserrat Torrebadell, Mireia Camós
Clinical and biological variables like genetic aberrations at diagnosis and the levels of measurable residual disease (MRD) are the most powerful biomarkers to predict the outcome of paediatric leukaemia. Recently, a model integrating the genetic abnormalities, transcriptional identity, and leukaemia stemness measured as leukaemic stem cell score (pLSC6) has been proposed to identify high-risk paediatric acute myeloid leukaemia (AML) patients. However, the role of epigenetics in defining prognosis still needs to be established...
March 23, 2023: British Journal of Haematology
https://read.qxmd.com/read/36916190/abemaciclib-drives-the-therapeutic-differentiation-of-acute-myeloid-leukaemia-stem-cells
#17
JOURNAL ARTICLE
Xiaoling Xie, Wuju Zhang, Xuan Zhou, Zhixin Ye, Hao Wang, Yingqi Qiu, Yating Pan, Yuxing Hu, Luyao Li, Zhuanzhuan Chen, Wanwen Yang, Yao Lu, Shuxin Zou, Yuhua Li, Xiaochun Bai
Self-renewal and differentiation arrest are two features of leukaemia stem cells (LSCs) responsible for the high relapse rate of acute myeloid leukaemia (AML). To screen drugs to overcome differentiation blockade for AML, we conducted screening of 2040 small molecules from a library of United States Food and Drug Administration-approved drugs and found that the cyclin-dependent kinase (CDK)4/6 inhibitor, abemaciclib, exerts high anti-leukaemic activity. Abemaciclib significantly suppressed proliferation and promoted the differentiation of LSCs in vitro...
March 14, 2023: British Journal of Haematology
https://read.qxmd.com/read/36894688/deletion-of-the-transcriptional-regulator-tfap4-accelerates-c-myc-driven-lymphomagenesis
#18
JOURNAL ARTICLE
Margaret A Potts, Shinsuke Mizutani, Alexandra L Garnham, Connie S N Li Wai Suen, Andrew J Kueh, Lin Tai, Martin Pal, Andreas Strasser, Marco J Herold
Many lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have been discovered and their functions characterised, DNA sequence data of primary patient samples suggest that many more do exist. However, the nature of their contributions to c-MYC driven lymphomagenesis have not yet been investigated. We identified TFAP4 as a potent suppressor of c-MYC driven lymphoma development in a previous genome-wide CRISPR knockout screen in primary cells in vivo [1]...
March 9, 2023: Cell Death and Differentiation
https://read.qxmd.com/read/36831387/anti-leukaemic-activity-of-rilpivirine-is-mediated-by-aurora-a-kinase-inhibition
#19
JOURNAL ARTICLE
Saiful Islam, Muhammed H Rahaman, Mingfeng Yu, Benjamin Noll, Jennifer H Martin, Shudong Wang, Richard Head
Acute myeloid leukaemia (AML) affects predominantly elderly people and has an incidence of 1% of all cancers and 2% of all cancer deaths. Despite using intensive chemotherapy and allogeneic stem cell transplantation, the treatment options for AML remain open for innovation. Thus, there is a need to explore alternative therapies such as less toxic targeted therapies in AML. Aurora A kinase is a well-established target for the treatment of various cancers, including AML. This kinase plays a pivotal role in the cell-division cycle, particularly in different stages of mitosis, and is also involved in many other cellular regulatory processes...
February 7, 2023: Cancers
https://read.qxmd.com/read/36764323/cyad-01-an-autologous-nkg2d-based-car-t-cell-therapy-in-relapsed-or-refractory-acute-myeloid-leukaemia-and-myelodysplastic-syndromes-or-multiple-myeloma-think-haematological-cohorts-of-the-dose-escalation-segment-of-a-phase-1-trial
#20
JOURNAL ARTICLE
David A Sallman, Tessa Kerre, Violaine Havelange, Xavier Poiré, Philippe Lewalle, Eunice S Wang, Jason B Brayer, Marco L Davila, Ine Moors, Jean-Pascal Machiels, Ahmad Awada, Erik M Alcantar-Orozco, Rossitza Borissova, Nathalie Braun, Marie-Sophie Dheur, David E Gilham, Caroline Lonez, Frédéric F Lehmann, Anne Flament
BACKGROUND: CYAD-01 is an autologous chimeric antigen receptor (CAR) T-cell product based on the natural killer (NK) group 2D (NKG2D) receptor, which binds eight ligands that are overexpressed in a wide range of haematological malignancies but are largely absent on non-neoplastic cells. Initial clinical evaluation of a single infusion of CYAD-01 at a low dose in patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, and multiple myeloma supported the feasibility of the approach and prompted further evaluation of CYAD-01...
March 2023: Lancet Haematology
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