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Leukaemic stem cell

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https://www.readbyqxmd.com/read/29780592/preleukemic-and-second-hit-mutational-events-in-an-acute-myeloid-leukemia-patient-with-a-novel-germline-runx1-mutation
#1
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/29769727/microbial-signals-drive-pre-leukaemic-myeloproliferation-in-a-tet2-deficient-host
#2
Marlies Meisel, Reinhard Hinterleitner, Alain Pacis, Li Chen, Zachary M Earley, Toufic Mayassi, Joseph F Pierre, Jordan D Ernest, Heather J Galipeau, Nikolaus Thuille, Romain Bouziat, Manuel Buscarlet, Daina L Ringus, Yitang Wang, Ye Li, Vu Dinh, Sangman M Kim, Benjamin D McDonald, Matthew A Zurenski, Mark W Musch, Glaucia C Furtado, Sergio A Lira, Gottfried Baier, Eugene B Chang, A Murat Eren, Christopher R Weber, Lambert Busque, Lucy A Godley, Elena F Verdú, Luis B Barreiro, Bana Jabri
Somatic mutations in tet methylcytosine dioxygenase 2 (TET2), which encodes an epigenetic modifier enzyme, drive the development of haematopoietic malignancies1-7 . In both humans and mice, TET2 deficiency leads to increased self-renewal of haematopoietic stem cells with a net developmental bias towards the myeloid lineage1,4,8,9 . However, pre-leukaemic myeloproliferation (PMP) occurs in only a fraction of Tet2-/- mice8,9 and humans with TET2 mutations1,3,5-7 , suggesting that extrinsic non-cell-autonomous factors are required for disease onset...
May 16, 2018: Nature
https://www.readbyqxmd.com/read/29769714/author-correction-a-myc-enhancer-cluster-regulates-normal-and-leukaemic-haematopoietic-stem-cell-hierarchies
#3
Carsten Bahr, Lisa von Paleske, Veli V Uslu, Silvia Remeseiro, Naoya Takayama, Stanley W Ng, Alex Murison, Katja Langenfeld, Massimo Petretich, Roberta Scognamiglio, Petra Zeisberger, Amelie S Benk, Ido Amit, Peter W Zandstra, Mathieu Lupien, John E Dick, Andreas Trumpp, François Spitz
In the originally published version of this Letter, ref. 43 was erroneously provided twice. In the 'Estimation of relative cell-type-specific composition of AML samples' section in the Methods, the citation to ref. 43 after the GEO dataset GSE24759 is correct. However, in the 'Mice' section of the Methods, the citation to ref. 43 after 'TAMERE' should have been associated with a new reference1. The original Letter has been corrected online (with the new reference included as ref. 49).
May 16, 2018: Nature
https://www.readbyqxmd.com/read/29743561/leukaemic-alterations-of-ikzf1-prime-stemness-and-malignancy-programs-in-human-lymphocytes
#4
Zhen Li, Shui-Ping Li, Ruo-Yan Li, Hua Zhu, Xia Liu, Xiao-Lin Guo, Li-Li Mu, Jie-Jing Cai, Fan Bai, Guo-Qiang Chen, Deng-Li Hong
Somatic cells acquire stem cell-like properties during cancerous transformation; however, mechanisms through which committed cells develop stemness and malignancy remain largely unknown. Here we uncovered upregulated stem cell program in leukaemic lymphoblasts of patients with IKZF1 alterations by analysing the archived gene-expression profiling datasets. We then used a frequent IKZF1 deletion, IK6, as a model via transduction into human primitive haematopoietic cells, followed by xenotransplantation in mice...
May 9, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29702522/three-dimensional-genome-organization-in-normal-and-malignant-haematopoiesis
#5
Sergi Cuartero, Matthias Merkenschlager
PURPOSE OF REVIEW: The three-dimensional organization of the genome inside the nucleus impacts on key aspects of genome function, including transcription, DNA replication and repair. The chromosome maintenance complex cohesin and the DNA binding protein CTCF cooperate to drive the formation of self-interacting topological domains. This facilitates transcriptional regulation via enhancer-promoter interactions, controls the distribution and release of torsional strain, and affects the frequency with which particular translocations arise, based on the spatial proximity of translocation partners...
April 26, 2018: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29599919/trib2-expression-in-granulocyte-monocyte-progenitors-drives-a-highly-drug-resistant-acute-myeloid-leukaemia-linked-to-elevated-bcl2
#6
Caitriona O'Connor, Krishna Yalla, Mara Salomé, Hothri Ananyambica Moka, Eduardo Gómez Castañeda, Patrick A Eyers, Karen Keeshan
Trib2 pseudokinase has oncogenic and tumour suppressive functions depending on the cellular context. We investigated the ability of Trib2 to transform different haemopoietic stem and progenitor cells (HSPCs). Our study identified the granulocyte-macrophage progenitor (GMP) subpopulation as a potent leukaemia initiating cell of Trib2-driven AML in vivo . Trib2 transformed GMPs generated a fully penetrant and short latency AML. AML cells expressing elevated Trib2 led to a chemoresistant phenotype following chemotherapy treatment...
March 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29342133/a-myc-enhancer-cluster-regulates-normal-and-leukaemic-haematopoietic-stem-cell-hierarchies
#7
Carsten Bahr, Lisa von Paleske, Veli V Uslu, Silvia Remeseiro, Naoya Takayama, Stanley W Ng, Alex Murison, Katja Langenfeld, Massimo Petretich, Roberta Scognamiglio, Petra Zeisberger, Amelie S Benk, Ido Amit, Peter W Zandstra, Mathieu Lupien, John E Dick, Andreas Trumpp, François Spitz
The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a 'super-enhancer' is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors...
January 25, 2018: Nature
https://www.readbyqxmd.com/read/29326122/gfi1b-a-key-player-in-the-genesis-and-maintenance-of-acute-myeloid-leukemia-and-myelodysplastic-syndrome
#8
Aniththa Thivakaran, Lacramioara Botezatu, Judith M Hönes, Judith Schütte, Lothar Vassen, Yahya S Al-Matary, Pradeep Patnana, Amos Zeller, Michael Heuser, Felicitas Thol, Razif Gabdoulline, Nadine Olberding, Daria Frank, Marina Suslo, Renata Köster, Klaus Lennartz, Andre Görgens, Bernd Giebel, Bertram Opalka, Ulrich Dührsen, Cyrus Khandanpour
Differentiation of hematopoietic stem cells is regulated by a concert of different transcription factors. Disturbed transcription factor function can be the basis of (pre)malignancies such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Growth factor independence 1b (Gfi1b) is a repressing transcription factor regulating quiescence of hematopoietic stem cells and differentiation of erythrocytes and platelets. Here, we show that low expression of Gfi1b in blast cells is associated with an inferior prognosis of MDS and AML patients...
April 2018: Haematologica
https://www.readbyqxmd.com/read/29211449/novel-reduced-graphene-oxide-zinc-silicate-calcium-silicate-electroconductive-biocomposite-for-stimulating-osteoporotic-bone-regeneration
#9
Kun Xiong, Tingting Wu, Qingbo Fan, Lin Chen, Minhao Yan
In the absence of external assistance, autogenous healing of bone fracture is difficult due to impaired regeneration ability under osteoporosis pathological conditions. In this study, a reduced graphene oxide/zinc silicate/calcium silicate (RGO/ZS/CS) conductive biocomposite with an optimal surface electroconductivity of 5625 S/m was prepared by a two-step spin-coating method. The presence of lamellar apatite nanocrystals on the surfaces of the biocomposite suggests that it has good in vitro biomineralization ability...
December 27, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29120027/humanised-mouse-models-for-haematopoiesis-and-infectious-diseases
#10
Veronika Lysenko, Donal McHugh, Lena Behrmann, Mary-Aude Rochat, Christian Matthias Wilk, Larisa Kovtonyuk, Jean-Pierre Bourquin, Christian Münz, Markus Gabriel Manz, Roberto Speck, Alexandre Theocharides
"Humanised" mouse models have emerged over past years as powerful tools for investigating human haematopoiesis and immunity. They allowed the identification of key factors for the maintenance and function of normal and leukaemic human haematopoietic stem cells. These findings have been widely used to dissect the pathogenesis of multiple myeloid and lymphoid neoplasms, such as acute myeloid leukaemia and acute lymphoblastic leukaemia. Furthermore, these models can serve as a stepping-stone to clinical trials by testing novel drugs that target leukaemic stem cells...
November 9, 2017: Swiss Medical Weekly
https://www.readbyqxmd.com/read/29065396/cd34-cd38-cd123-cells-are-present-in-virtually-all-acute-myeloid-leukaemia-blasts-a-promising-single-unique-phenotype-for-minimal-residual-disease-detection
#11
Adhra Al-Mawali, Avinash Daniel Pinto, Shoaib Al-Zadjali
BACKGROUND/AIMS: In CD34-positive acute myeloid leukaemia (AML), the leukaemia-initiating event likely takes place in the CD34+CD38- cell compartment. CD123 has been shown to be a unique marker of leukaemic stem cells within the CD34+CD38- compartment. The aim of this study was to identify the percentage of CD34+CD38-CD123+ cells in AML blasts, AML CD34+CD38- stem cells, and normal and regenerating bone marrow CD34+CD38- stem cells from non-myeloid malignancies. METHODS: Thirty-eight adult de novo AML patients with intention to treat were enrolled after the application of inclusion criteria from February 2012 to February 2017...
2017: Acta Haematologica
https://www.readbyqxmd.com/read/29035359/acute-myeloid-leukaemia-disrupts-endogenous-myelo-erythropoiesis-by-compromising-the-adipocyte-bone-marrow-niche
#12
Allison L Boyd, Jennifer C Reid, Kyle R Salci, Lili Aslostovar, Yannick D Benoit, Zoya Shapovalova, Mio Nakanishi, Deanna P Porras, Mohammed Almakadi, Clinton J V Campbell, Michael F Jackson, Catherine A Ross, Ronan Foley, Brian Leber, David S Allan, Mitchell Sabloff, Anargyros Xenocostas, Tony J Collins, Mickie Bhatia
Acute myeloid leukaemia (AML) is distinguished by the generation of dysfunctional leukaemic blasts, and patients characteristically suffer from fatal infections and anaemia due to insufficient normal myelo-erythropoiesis. Direct physical crowding of bone marrow (BM) by accumulating leukaemic cells does not fully account for this haematopoietic failure. Here, analyses from AML patients were applied to both in vitro co-culture platforms and in vivo xenograft modelling, revealing that human AML disease specifically disrupts the adipocytic niche in BM...
November 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/29017180/targeting-apoptosis-in-acute-myeloid-leukaemia
#13
REVIEW
Philippe A Cassier, Marie Castets, Amine Belhabri, Norbert Vey
Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease, and its incidence is increasing as the populations in Western countries age. Despite major advances in understanding the genetic landscape of AML and its impact on the biology of the disease, standard therapy has not changed significantly in the last three decades. Allogeneic haematopoietic stem cell transplantation remains the best chance for cure, but can only be offered to a minority of younger fit patients. Molecularly targeted drugs aiming at restoring apoptosis in leukaemic cells have shown encouraging activity in early clinical trials and some of these drugs are currently being evaluated in randomised controlled trials...
October 10, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28854169/a-somatic-mutation-in-erythro-myeloid-progenitors-causes-neurodegenerative-disease
#14
Elvira Mass, Christian E Jacome-Galarza, Thomas Blank, Tomi Lazarov, Benjamin H Durham, Neval Ozkaya, Alessandro Pastore, Marius Schwabenland, Young Rock Chung, Marc K Rosenblum, Marco Prinz, Omar Abdel-Wahab, Frederic Geissmann
The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS-MEK-ERK pathway such as BRAF(V600E), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration...
September 21, 2017: Nature
https://www.readbyqxmd.com/read/28825709/ascorbate-regulates-haematopoietic-stem-cell-function-and-leukaemogenesis
#15
Michalis Agathocleous, Corbin E Meacham, Rebecca J Burgess, Elena Piskounova, Zhiyu Zhao, Genevieve M Crane, Brianna L Cowin, Emily Bruner, Malea M Murphy, Weina Chen, Gerald J Spangrude, Zeping Hu, Ralph J DeBerardinis, Sean J Morrison
Stem-cell fate can be influenced by metabolite levels in culture, but it is not known whether physiological variations in metabolite levels in normal tissues regulate stem-cell function in vivo. Here we describe a metabolomics method for the analysis of rare cell populations isolated directly from tissues and use it to compare mouse haematopoietic stem cells (HSCs) to restricted haematopoietic progenitors. Each haematopoietic cell type had a distinct metabolic signature. Human and mouse HSCs had unusually high levels of ascorbate, which decreased with differentiation...
September 28, 2017: Nature
https://www.readbyqxmd.com/read/28658204/tracing-the-origins-of-relapse-in-acute-myeloid-leukaemia-to-stem-cells
#16
Liran I Shlush, Amanda Mitchell, Lawrence Heisler, Sagi Abelson, Stanley W K Ng, Aaron Trotman-Grant, Jessie J F Medeiros, Abilasha Rao-Bhatia, Ivana Jaciw-Zurakowsky, Rene Marke, Jessica L McLeod, Monica Doedens, Gary Bader, Veronique Voisin, ChangJiang Xu, John D McPherson, Thomas J Hudson, Jean C Y Wang, Mark D Minden, John E Dick
In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy...
July 6, 2017: Nature
https://www.readbyqxmd.com/read/28650479/aml1-eto-requires-enhanced-c-d-box-snorna-rnp-formation-to-induce-self-renewal-and-leukaemia
#17
Fengbiao Zhou, Yi Liu, Christian Rohde, Cornelius Pauli, Dennis Gerloff, Marcel Köhn, Danny Misiak, Nicole Bäumer, Chunhong Cui, Stefanie Göllner, Thomas Oellerich, Hubert Serve, Maria-Paz Garcia-Cuellar, Robert Slany, Jaroslaw P Maciejewski, Bartlomiej Przychodzen, Barbara Seliger, Hans-Ulrich Klein, Christoph Bartenhagen, Wolfgang E Berdel, Martin Dugas, Makoto Mark Taketo, Daneyal Farouq, Schraga Schwartz, Aviv Regev, Josée Hébert, Guy Sauvageau, Caroline Pabst, Stefan Hüttelmaier, Carsten Müller-Tidow
Leukaemogenesis requires enhanced self-renewal, which is induced by oncogenes. The underlying molecular mechanisms remain incompletely understood. Here, we identified C/D box snoRNAs and rRNA 2'-O-methylation as critical determinants of leukaemic stem cell activity. Leukaemogenesis by AML1-ETO required expression of the groucho-related amino-terminal enhancer of split (AES). AES functioned by inducing snoRNA/RNP formation via interaction with the RNA helicase DDX21. Similarly, global loss of C/D box snoRNAs with concomitant loss of rRNA 2'-O-methylation resulted in decreased leukaemia self-renewal potential...
July 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28593997/severe-congenital-neutropenias
#18
REVIEW
Julia Skokowa, David C Dale, Ivo P Touw, Cornelia Zeidler, Karl Welte
Severe congenital neutropenias are a heterogeneous group of rare haematological diseases characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life. The most frequent pathogenic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte colony-stimulating factor (G-CSF) signalling pathway...
June 8, 2017: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/28579852/treatment-of-myelofibrosis-old-and-new-strategies
#19
REVIEW
Alessandra Iurlo, Daniele Cattaneo
Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm that is mainly characterised by reactive bone marrow fibrosis, extramedullary haematopoiesis, anaemia, hepatosplenomegaly, constitutional symptoms, leukaemic progression, and shortened survival. As such, this malignancy is still orphan of curative treatments; indeed, the only treatment that has a clearly demonstrated impact on disease progression is allogeneic haematopoietic stem cell transplantation, but only a minority of patients are eligible for such intensive therapy...
2017: Clinical Medicine Insights. Blood Disorders
https://www.readbyqxmd.com/read/28556984/the-emerging-role-of-anti-cd25-directed-therapies-as-both-immune-modulators-and-targeted-agents-in-cancer
#20
REVIEW
Michael J Flynn, John A Hartley
CD25 (also termed IL2RA) forms one component of the high-affinity heterotrimeric interleukin 2 (IL2) receptor on activated T cells. Its affinity for IL2 and cellular function are tightly regulated and vary in different cell types. The high frequency of CD25 on the surface of many different haematological tumour cells is now well established and, apart from its prognostic significance, CD25 may be present on leukaemic stem cells and enable oncogenic signalling pathways in leukaemic cells. Additionally, high CD25 expression in activated circulating immune cells and Tregs is a factor that has already been exploited by IL2 immunotherapies for treatment of tumours and autoimmune disease...
October 2017: British Journal of Haematology
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