References of "Asnafi, Vahid"
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See detailImproved high throughput DNA-seq based mapping of HTLV-1 integration sites: a tool to define response to treatment, ATL prognosis and guide therapeutic strategies
Marçais, Ambroise; Artesi, Maria ULiege; Durkin, Keith ULiege et al

Conference (2017)

Background Adult T-cell leukemia/lymphoma (ATL) is an aggressive CD4+ T-cell malignancy caused by HTLV-1 infection and associated with extremely poor prognosis. In France, treatment strategies mainly ... [more ▼]

Background Adult T-cell leukemia/lymphoma (ATL) is an aggressive CD4+ T-cell malignancy caused by HTLV-1 infection and associated with extremely poor prognosis. In France, treatment strategies mainly include chemotherapy, antiviral therapy and allogeneic stem cell transplantation, based on clinical subtype and therapeutic responses. Response to treatment is evaluated based on consensus criteria defined in 2009 (Tsukasaki K, Hermine O et al, JCO 2009). Although immuno-phenotyping, TCRγ rearrangement and HTLV-1 proviral load (PVL) quantification are often assayed, complete clinical remission (CR) is currently defined by morphological and cytological criteria i.e. complete blood cell counts (CBC) and the presence of abnormal lymphocytes. Given the extremely poor prognosis and high rates of early relapse, a revision of the response criteria is required, calling for improved tools that integrate specific aspects of the pathophysiology of ATL to better estimate response to treatment. Methods We retrospectively analyzed longitudinal PBMC samples from 6 ATL patients diagnosed with a leukemic subtype (5 acute and 1 chronic-aggressive) which all achieved CR upon therapy, yet relapsed after a median time of 15,9 months (range 2,4-70,7). CR was assessed by morphological and cytological criteria. An improved high throughput sequencing (HTS) based method was utilized to map and quantify the abundance of HTLV-1 genomic integration sites (IS), overcoming some of the limitations of previously published protocols. The dynamic range was increased by assaying both the 5’LTR and 3’LTRs, allowing better determination of clone abundance and revealing 5’ deletions. An enrichment step limited PCR duplicates. The addition of off-the-shelf Illumina primers simplified library multiplexing and reduced the costs to the point where the protocol could be applied to a clinical setting. Results HTS- mapping of HTLV-1 IS at diagnosis revealed in all cases a unique IS that constituted 92-99% of proviral genomes, with PVLs of 33-510%. All patients were treated and achieved CR which was characterized by normalized CBC, <5% abnormal lymphocytes and the absence of measurable tumors for >4 weeks. For 3/6 patients, the clone frequency distribution of HTLV-1 infected cells at CR was composed of multiple low abundance clones, of which the unique presumed malignant IS contributed to less than 2% of proviral genomes. In contrast, clonality analysis of the remaining 3/6 patients revealed that the relative abundance of the malignant clone detected at diagnosis remained dominant at CR (36-83% of PVL), despite clinical response criteria typical of CR and a 3-20-fold decrease in PVLs. These patients relapsed after 2.4, 2.9 and 3.4 months respectively with a dominant malignant clone >95% while patients with a polyclonal architecture showed significantly longer CR (28, 59 and 71 months). Conclusions Our observations highlight the great heterogeneity within an identical CR group, underlining the need for revisiting response criteria for ATL. Our results call for the use of this improved HTS-based method to measure HTLV-1 clonality as a tool to better estimate response to treatment, predict relapse and guide therapeutic choices in the course of treatment. [less ▲]

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See detailHuman bone marrow adipocytes block granulopoiesis through neuropilin-1-induced granulocyte colony-stimulating factor inhibition.
Belaid-Choucair, Zakia ULiege; Lepelletier, Yves; Poncin, Géraldine ULiege et al

in Stem Cells (2008), 26(6), 1556-64

Adipocytes are part of hematopoietic microenvironment, even though up to now in humans, their role in hematopoiesis is still questioned. We have previously shown that accumulation of fat cells in femoral ... [more ▼]

Adipocytes are part of hematopoietic microenvironment, even though up to now in humans, their role in hematopoiesis is still questioned. We have previously shown that accumulation of fat cells in femoral bone marrow (BM) coincides with increased expression of neuropilin-1 (NP-1), while it is weakly expressed in hematopoietic iliac crest BM. Starting from this observation, we postulated that adipocytes might exert a negative effect on hematopoiesis mediated through NP-1. To test this hypothesis, we set up BM adipocytes differentiated into fibroblast-like fat cells (FLFC), which share the major characteristics of primitive unilocular fat cells, as an experimental model. As expected, FLFCs constitutively produced macrophage colony stimulating factor and induced CD34(+) differentiation into macrophages independently of cell-to-cell contact. By contrast, granulopoiesis was hampered by cell-to-cell contact but could be restored in transwell culture conditions, together with granulocyte colony stimulating factor production. Both functions were also recovered when FLFCs cultured in contact with CD34(+) cells were treated with an antibody neutralizing NP-1, which proved its critical implication in contact inhibition. An inflammatory cytokine such as interleukin-1 beta or dexamethasone modulates FLFC properties to restore granulopoiesis. Our data provide the first evidence that primary adipocytes exert regulatory functions during hematopoiesis that might be implicated in some pathological processes. Disclosure of potential conflicts of interest is found at the end of this article. [less ▲]

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See detailHuman erythroleukemia: is the two-hit model of mouse leukemogenesis valid in human disease?
Coulon, Séverine; Vandekerckhove, Julie; Dussiot, Michael et al

in Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K (2007)

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