Functional Alterations of Lin−CD34+CD38+ Progenitors in Chronic Myelomonocytic Leukaemia and on Progression to Acute Leukaemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4119-4119
Author(s):  
Qian Sun ◽  
Chi-Chiu So ◽  
Sze-Fai Yip ◽  
Thomas S.K. Wan ◽  
Edmond Shiu Kwan Ma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Acquired Resistance ◽  
Differentiation Potential ◽  
Cd34 Cells ◽  
Cell Disorder ◽  
Chronic Myelomonocytic Leukaemia ◽  
Acute Myeloid

Abstract Chronic myelomonocytic leukaemia (CMML) is a clonal bone marrow stem cell disorder based on the presence of trilineage involvement, the association of myelodysplastic and myeloproliferative features and its ability to transform into acute myeloid leukaemia. The objectives of our study are to identify the cell population and its functional characteristics involved in evolution from CMML phase to acute myeloid leukaemia. We analysed Lin−CD34+ stem/progenitor population and performed cell proliferation, apoptotic assays, self-renewal ability and differentiation potential studies in purified populations of Lin−CD34+CD38− stem cells and Lin−CD34+CD38+ committed progenitors from peripheral blood of 16 patients with CMML and in six of the 16 after transformation to acute myeloid leukaemia (AML-t). We observed an expansion of the stem cell/progenitor pool (Lin−CD34+ cells) in AML-t comprising mainly of Lin−CD34+CD38+ committed progenitors within Lin−CD34+ cells. The Lin−CD34+CD38+ committed progenitors displayed highly proliferative activity in CMML and in AML-t; and additionally acquired resistance to apotosis and myeloid colony self-renewing ability in AML-t. Impairment of dendritic cell (DC) differentiation was observed with complete block in AML-t. Our findings suggest Lin−CD34+CD38+ committed progenitors instead of Lin−CD34+CD38− stem cells could be the target(s) of secondary genetic lesions underpinning progression from CMML to AML. These results have implications for the further study of the biology of leukaemic transformation and the design of new strategies for the effective treatment of CMML.

scholarly journals Adhesion Molecules Involved in Stem Cell Niche Retention During Normal Haematopoiesis and in Acute Myeloid Leukaemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Julien M. P. Grenier ◽  
Céline Testut ◽  
Cyril Fauriat ◽  
Stéphane J. C. Mancini ◽  
Michel Aurrand-Lions
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Stem Cell ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Adhesion Molecules ◽  
Molecular Mechanisms ◽  
Genetically Engineered ◽  
Cell Niche ◽  
Acute Myeloid

In the bone marrow (BM) of adult mammals, haematopoietic stem cells (HSCs) are retained in micro-anatomical structures by adhesion molecules that regulate HSC quiescence, proliferation and commitment. During decades, researchers have used engraftment to study the function of adhesion molecules in HSC’s homeostasis regulation. Since the 90’s, progress in genetically engineered mouse models has allowed a better understanding of adhesion molecules involved in HSCs regulation by BM niches and raised questions about the role of adhesion mechanisms in conferring drug resistance to cancer cells nested in the BM. This has been especially studied in acute myeloid leukaemia (AML) which was the first disease in which the concept of cancer stem cell (CSC) or leukemic stem cells (LSCs) was demonstrated. In AML, it has been proposed that LSCs propagate the disease and are able to replenish the leukemic bulk after complete remission suggesting that LSC may be endowed with drug resistance properties. However, whether such properties are due to extrinsic or intrinsic molecular mechanisms, fully or partially supported by molecular crosstalk between LSCs and surrounding BM micro-environment is still matter of debate. In this review, we focus on adhesion molecules that have been involved in HSCs or LSCs anchoring to BM niches and discuss if inhibition of such mechanism may represent new therapeutic avenues to eradicate LSCs.

scholarly journals Differences between intrinsic and acquired nucleoside analogue resistance in acute myeloid leukaemia cells

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Tamara Rothenburger ◽  
Dominique Thomas ◽  
Yannick Schreiber ◽  
Paul R. Wratil ◽  
Tamara Pflantz ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cell Lines ◽  
Nucleoside Analogue ◽  
Acquired Resistance ◽  
Nucleoside Analogues ◽  
Cross Resistance ◽  
Enzymatic Assays ◽  
Anti Cancer ◽  
Acute Myeloid

Abstract Background SAMHD1 mediates resistance to anti-cancer nucleoside analogues, including cytarabine, decitabine, and nelarabine that are commonly used for the treatment of leukaemia, through cleavage of their triphosphorylated forms. Hence, SAMHD1 inhibitors are promising candidates for the sensitisation of leukaemia cells to nucleoside analogue-based therapy. Here, we investigated the effects of the cytosine analogue CNDAC, which has been proposed to be a SAMHD1 inhibitor, in the context of SAMHD1. Methods CNDAC was tested in 13 acute myeloid leukaemia (AML) cell lines, in 26 acute lymphoblastic leukaemia (ALL) cell lines, ten AML sublines adapted to various antileukaemic drugs, 24 single cell-derived clonal AML sublines, and primary leukaemic blasts from 24 AML patients. Moreover, 24 CNDAC-resistant sublines of the AML cell lines HL-60 and PL-21 were established. The SAMHD1 gene was disrupted using CRISPR/Cas9 and SAMHD1 depleted using RNAi, and the viral Vpx protein. Forced DCK expression was achieved by lentiviral transduction. SAMHD1 promoter methylation was determined by PCR after treatment of genomic DNA with the methylation-sensitive HpaII endonuclease. Nucleoside (analogue) triphosphate levels were determined by LC-MS/MS. CNDAC interaction with SAMHD1 was analysed by an enzymatic assay and by crystallisation. Results Although the cytosine analogue CNDAC was anticipated to inhibit SAMHD1, SAMHD1 mediated intrinsic CNDAC resistance in leukaemia cells. Accordingly, SAMHD1 depletion increased CNDAC triphosphate (CNDAC-TP) levels and CNDAC toxicity. Enzymatic assays and crystallisation studies confirmed CNDAC-TP to be a SAMHD1 substrate. In 24 CNDAC-adapted acute myeloid leukaemia (AML) sublines, resistance was driven by DCK (catalyses initial nucleoside phosphorylation) loss. CNDAC-adapted sublines displayed cross-resistance only to other DCK substrates (e.g. cytarabine, decitabine). Cell lines adapted to drugs not affected by DCK or SAMHD1 remained CNDAC sensitive. In cytarabine-adapted AML cells, increased SAMHD1 and reduced DCK levels contributed to cytarabine and CNDAC resistance. Conclusion Intrinsic and acquired resistance to CNDAC and related nucleoside analogues are driven by different mechanisms. The lack of cross-resistance between SAMHD1/ DCK substrates and non-substrates provides scope for next-line therapies after treatment failure.

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.

scholarly journals Applicability and reproducibility of acute myeloid leukaemia stem cell assessment in a multi‐centre setting

2020 ◽  
Vol 190 (6) ◽  
pp. 891-900 ◽  
Author(s):  
Diana Hanekamp ◽  
Alexander N. Snel ◽  
Angèle Kelder ◽  
Willemijn J. Scholten ◽  
Naeem Khan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Acute Myeloid
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