scholarly journals Investigating the Link Between Trisomy 21 and Acquired Mutations in the GATA1 Gene

The Physician ◽  
2019 ◽  
Vol 6 (1) ◽  
pp. c9
Author(s):  
Triya Chakravorty ◽  
Irene Roberts
Keyword(s):  
Down Syndrome ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Trisomy 21 ◽  
Children With Down Syndrome ◽  
Transient Abnormal Myelopoiesis ◽  
Increased Risk ◽  
Leukaemic Cells ◽  
Acute Myeloid

Children with Down syndrome (DS) due to trisomy 21 (T21) are at an increased risk of developing the neonatal preleukaemic disorder transient abnormal myelopoiesis (TAM), which may transform into childhood acute myeloid leukaemia (ML-DS). Leukaemic cells in TAM and ML-DS have acquired mutations in the GATA1 gene. Although it is clear that acquired mutations in GATA1 are necessary for the development of TAM and ML-DS, questions remain concerning the mechanisms of disease.

scholarly journals Macrophages in Acute Myeloid Leukaemia: Significant Players in Therapy Resistance and Patient Outcomes

2021 ◽  
Vol 9 ◽  
Author(s):  
Katerina E. Miari ◽  
Monica L. Guzman ◽  
Helen Wheadon ◽  
Mark T. S. Williams
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Clinical Outcomes ◽  
Patient Outcomes ◽  
Therapy Resistance ◽  
Research Field ◽  
Cell Death Pathways ◽  
Leukaemic Cells ◽  
Acute Myeloid

Acute Myeloid Leukaemia (AML) is a commonly occurring severe haematological malignancy, with most patients exhibiting sub-optimal clinical outcomes. Therapy resistance significantly contributes towards failure of traditional and targeted treatments, disease relapse and mortality in AML patients. The mechanisms driving therapy resistance in AML are not fully understood, and approaches to overcome therapy resistance are important for curative therapies. To date, most studies have focused on therapy resistant mechanisms inherent to leukaemic cells (e.g., TP53 mutations), overlooking to some extent, acquired mechanisms of resistance through extrinsic processes. In the bone marrow microenvironment (BMME), leukaemic cells interact with the surrounding bone resident cells, driving acquired therapy resistance in AML. Growing evidence suggests that macrophages, highly plastic immune cells present in the BMME, play a role in the pathophysiology of AML. Leukaemia-supporting macrophage subsets (CD163+CD206+) are elevated in preclinical in vivo models of AML and AML patients. However, the relationship between macrophages and therapy resistance in AML warrants further investigation. In this review, we correlate the potential links between macrophages, the development of therapy resistance, and patient outcomes in AML. We specifically focus on macrophage reprogramming by AML cells, macrophage-driven activation of anti-cell death pathways in AML cells, and the association between macrophage phenotypes and clinical outcomes in AML, including their potential prognostic value. Lastly, we discuss therapeutic targeting of macrophages, as a strategy to circumvent therapy resistance in AML, and discuss how emerging genomic and proteomic-based approaches can be utilised to address existing challenges in this research field.

Myelodysplastic Syndrome, Myeloid Leukaemia of Down Syndrome, and Juvenile Myelomonocytic Leukaemia

2020 ◽  
pp. 134-141
Author(s):  
Henrik Hasle ◽  
Charlotte M. Niemeyer
Keyword(s):  
Bone Marrow ◽  
Down Syndrome ◽  
Stem Cell ◽  
Acute Myeloid Leukaemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukaemia ◽  
Clinical Characteristics ◽  
Bone Marrow Failure ◽  
Signal Pathways ◽  
Acute Myeloid

Myeloid malignancies in children are divided into acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS), juvenile myelomonocytic leukaemia (JMML), and the myeloid leukaemia of Down syndrome (ML-DS). Predisposing genetic conditions are common in MDS. Differentiating MDS from inherited bone marrow failure or AML may be challenging. Therapy consists of observation, immunosuppression, or stem-cell transplantation (SCT). Germline and somatic mutations deregulating the Ras/MAPK signal pathways are key initiating events in JMML. Genetics in JMML defines clinically relevant subgroups and indications for SCT. ML-DS presents with unique clinical characteristics and responds favourably to reduced doses of AML chemotherapy; however, relapse is often refractory to therapy.

Anti-natural Killer Inhibitory Receptors in Elderly Patients with Acute Myeloid Leukaemia

2010 ◽  
Vol 06 (01) ◽  
pp. 86
Author(s):  
Norbert Vey ◽  
Daniel Olive ◽  
◽  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Single Agent ◽  
Inhibitory Receptors ◽  
Leukaemic Cells ◽  
Acute Myeloid

Treatment with anti-killer-cell immunoglobulin-like receptor (KIR) monoclonal antibody (mAb) is a new approach aimed at harnessing the antileukaemic potential of natural killer (NK) cells for the treatment of acute myeloid leukaemia (AML). NK cell antitumour activity is regulated by a balance between activating and inhibitory receptors (KIR). 1-7F9/IPH2101 is a fully human immunoglobulin G4 (IgG4) mAb that binds to inhibitory KIR and blocks binding with its ligand (human leukocyte antigen C [HLA-C] molecule) on leukaemic cells.In vitro,and in a surrogatein vivomodel in mice, treatment with 1-7F9/IPH2101 was able to induce NK cell activation and cytotoxicity against leukaemic cells. Patients with AML often display abnormal NK cell function, while evidence of an impact of NK cell status on AML outcome has been reported in allogeneic transplantation. 1-7F9/IPH2101 is currently under clinical investigation in patients with AML. This article reviews the mechanisms of NK cell antileukaemic activity and its role and defects in AML. Currently available data on the pre-clinical and clinical development of 1-7F9/IPH2101 are presented, and the rationale for its future use as a single agent or in combination is discussed.

scholarly journals Two Novel GATA1 Mutations in Transient Abnormal Myelopoiesis of Thai Neonates with Down Syndrome

2019 ◽  
Vol 08 (04) ◽  
pp. 187-192
Author(s):  
Kanokporn Chukua ◽  
Chayanont Netsawang ◽  
Kittipoom Padungthai ◽  
Thanitchet Khetkham ◽  
Piyaporn Chokevittaya ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Down Syndrome ◽  
Risk Factor ◽  
Myeloid Leukemia ◽  
Heterozygous Mutation ◽  
Frameshift Mutations ◽  
Children With Down Syndrome ◽  
Transient Abnormal Myelopoiesis ◽  
Nucleotide Insertion ◽  
Acute Myeloid

AbstractChildren with Down syndrome (DS) are 150 times more likely to develop acute myeloid leukemia (ML-DS), compared with those without. One risk factor is transient abnormal myelopoiesis (TAM). Somatic truncating GATA1 mutations are found in most TAM patients and are markers for future ML-DS. We identified two novel frameshift mutations in our seven newborns with DS and TAM: a heterozygous mutation of 17 nucleotide duplication (c.154_170 dup) and a heterozygous 9-nucleotide deletion combined with a 2-nucleotide insertion (c.150_158delins CT). Both mutations introduced a truncated GATA1 protein. Thus, neonates with DS and TAM require frequent ML-DS monitoring.

In vitro culture of clonogenic leukaemic cells in acute myeloid leukaemia: growth pattern and drug sensitivity

1983 ◽  
Vol 55 (3) ◽  
pp. 427-437 ◽  
Author(s):  
Jean-Pierre Marie ◽  
Robert Zittoun ◽  
Danielle Thevenin ◽  
Monique Mathieu ◽  
Franck Viguie
Keyword(s):  
Acute Myeloid Leukaemia ◽  
In Vitro Culture ◽  
Myeloid Leukaemia ◽  
Growth Pattern ◽  
Drug Sensitivity ◽  
Leukaemic Cells ◽  
Acute Myeloid

scholarly journals Increased cellular hypoxia and reduced proliferation of both normal and leukaemic cells during progression of acute myeloid leukaemia in rats

2000 ◽  
Vol 33 (6) ◽  
pp. 381-395 ◽  
Author(s):  
P.Ø. Jensen ◽  
B.T. Mortensen ◽  
R.J. Hodgkiss ◽  
P.O. Iversen ◽  
I.J. Christensen ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Leukaemic Cells ◽  
Cellular Hypoxia ◽  
Acute Myeloid

Acute Myeloid Leukaemia

2020 ◽  
pp. 124-133
Author(s):  
Gertjan Kaspers ◽  
Dirk Reinhardt
Keyword(s):  
Down Syndrome ◽  
Stem Cell ◽  
Prognostic Factors ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Residual Disease ◽  
Study Groups ◽  
Cooperative Study ◽  
Minimal Residual ◽  
Acute Myeloid

Acute myeloid leukaemia (AML) is the second most frequent type of leukaemia in children, and is cured nowadays in about 75% of patients in settings with essentially unlimited resources. This chapter discusses the aetiology and epidemiology of this interesting disease, its typical clinical presentation, diagnostics, and biology. The classifications, prognostic factors, and risk stratification (including minimal residual disease), and AML treatment (covering chemotherapy and allogeneic stem-cell transplantation) is presented. Several practical illustrations are included, and results of recent studies from the main cooperative study groups are summarized. Finally, side effects during treatment and late effects, as well as acute promyelocytic leukaemia (APL) and myeloid leukaemia of Down syndrome (ML-DS), are discussed. The chapter concludes with the actual challenges and perspectives.

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