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A Dalloul

Publications and source records attributed to A Dalloul.

12 recordsLinked to original sources
PubMed2006

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL)-B-cells are quiescent differentiated cells that produce interleukin (IL)-10 and accumulate due to resistance to apoptosis. The mechanisms underlying such resistance are poorly understood. Herein we show that all CLL B-cells tested (30/30) display high mRNA and protein expression of the tumor suppressor Mda-7/IL-24, an IL-10 family member, in comparison to normal B cells. A downstream Mda-7 signaling target, p38 mitogen-activated protein kinase (MAPK) was highly phosphorylated in all CLL cells but not in normal B-cells. Mda-7 expression and p38 MAPK phosphorylation diminished in culture and the latter could be reinduced by recombinant (r)-IL-24 or LPS and Mda-7 transfection. Mda-7/IL-24 siRNA specifically inhibited p38 MAPK phosphorylation in CLL without affecting p38 MAPK, bcl2, or Lyn expression, further demonstrating the direct role of Mda-7/IL-24 in p38 MAPK activation. Both pharmacological inhibition of p38 MAPK and Mda-7 silencing augmented spontaneous apoptosis by three-fold in CLL cells cultured in autologous serum, which was reversed by LPS and r-IL-24. We established the role of p38 MAPK in CLL cell survival and demonstrated a paradoxical effect, whereby Mda-7 and IL-24, inducers of apoptosis in diverse cancer cells, promote the survival of CLL B-cells through p38 MAPK activation.

Aged↗
PubMed2002

Aiolos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation.

Aiolos and Ikaros encode hemopoietic-specific zinc finger transcription factors that are important regulators of lymphocyte differentiation. Aiolos and Ikaros play a critical role in regulating B and T cell development. Gene targeting studies in mice have shown that inactivation of Ikaros family proteins leads to a complete absence of T, B, NK and dendritic cells, whereas a reduction of Ikaros activity induce hyperproliferation and lymphomas. Aiolos knock-out mice have quantitatively normal lymphoid cells but have chronically activated B cells producing autoantibodies and develop lymphomas with increased frequency. These proteins are involved in the control of gene expression and, associated to nuclear complexes, participate in nucleosome remodeling. This protein family governs cell fate decisions and regulates homeostasis through complex isoforms expression and dimerization. Changes in this regulatory network may reflect differentiation and proliferation adjustments made in lymphoid progenitors and precursors. The direct involvement of aberrant Ikaros protein expression in human hematological oncogenesis, although suggested by several studies, remains to be settled at the genomic level. These points will be discussed in the present review.

Amino Acid Sequence↗
PubMed2001

Forced expression of the Ikaros 6 isoform in human placental blood CD34(+) cells impairs their ability to differentiate toward the B-lymphoid lineage.

Studies in mice suggest that the Ikaros (Ik) gene encodes several isoforms and is a critical regulator of hematolymphoid differentiation. Little is known on the role of Ikaros in human stem cell differentiation. Herein, the biological consequences of the forced expression of Ikaros 6 (Ik6) in human placental blood CD34(+) progenitors are evaluated. Ik6 is one of the isoforms produced from the Ikaros premessenger RNA by alternative splicing and is thought to behave as a dominant negative isoform of the gene product because it lacks the DNA binding domain present in transcriptionally active isoforms. The results demonstrate that human cord blood CD34(+) cells that express high levels of Ik6 as a result of retrovirally mediated gene transfer have a reduced capacity to produce lymphoid B cells in 2 independent assays: (1) in vitro reinitiation of human hematopoiesis during coculture with the MS-5 murine stromal cell line and (2) xenotransplantation in nonobese diabetic-severe combined immunodeficient mice. These results suggest that Ikaros plays an important role in stem cell commitment in humans and that the balance between the different isoforms is a key element of this regulatory system; they support the hypothesis that posttranscriptional events can participate in the control of human hematopoietic differentiation.

Animals↗
PubMed2000

Characterization of dendritic cell differentiation pathways from cord blood CD34(+)CD7(+)CD45RA(+) hematopoietic progenitor cells.

To better characterize human dendritic cells (DCs) that originate from lymphoid progenitors, the authors examined the DC differentiation pathways from a novel CD7(+)CD45RA(+) progenitor population found among cord blood CD34(+) cells. Unlike CD7(-)CD45RA(+) and CD7(+)CD45RA(-) progenitors, this population displayed high natural killer (NK) cell differentiation capacity when cultured with stem cell factor (SCF), interleukin (IL)-2, IL-7, and IL-15, attesting to its lymphoid potential. In cultures with SCF, Flt3 ligand (FL), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-alpha (standard condition), CD7(+)CD45RA(+) progenitors expanded less (37- vs 155-fold) but yielded 2-fold higher CD1a(+) DC percentages than CD7(-)CD45RA(+) or CD7(+)CD45RA(-) progenitors. As reported for CD34(+)CD1a(-) thymocytes, cloning experiments demonstrated that CD7(+)CD45RA(+) cells comprised bipotent NK/DC progenitors. DCs differentiated from CD7(-)CD45RA(+) and CD7(+)CD45RA(+) progenitors differed as to E-cadherin CD123, CD116, and CD127 expression, but none of these was really discriminant. Only CD7(+)CD45RA(+) or thymic progenitors differentiated into Lag(+)S100(+) Langerhans cells in the absence of exogenous transforming growth factor (TGF)-beta 1. Analysis of the DC differentiation pathways showed that CD7(+)CD45RA(+) progenitors generated CD1a(+)CD14(-) precursors that were macrophage-colony stimulating factor (M-CSF) resistant and CD1a(-)CD14(+) precursors that readily differentiated into DCs under the standard condition. Accordingly, CD7(+)CD45RA(+) progenitor-derived mature DCs produced 2- to 4-fold more IL-6, IL-12, and TNF-alpha on CD40 ligation and elicited 3- to 6-fold higher allogeneic T-lymphocyte reactivity than CD7(-)CD45RA(+) progenitor-derived DCs. Altogether, these findings provide evidence that the DCs that differentiate from cord blood CD34(+)CD7(+)CD45RA(+) progenitors represent an original population for their developmental pathways and function. (Blood. 2000;96:3748-3756)

Adult↗
PubMed2000

The pseudo-immunoreceptor tyrosine-based activation motif of CD5 mediates its inhibitory action on B-cell receptor signaling.

Genetic studies revealed that CD5 could be a negative regulator of the B-cell antigen receptor (BCR). We explore here the effect of human CD5 on BCR-triggered responses. B cells were obtained expressing a chimera composed of extracellular and transmembrane domains of Fcgamma type IIB receptor fused to CD5 cytoplasmic domain (CD5cyt). Coligation of the chimera with the BCR induces CD5cyt tyrosine phosphorylation. A rapid inhibition of BCR-induced calcium response is observed, as well as a partial but delayed inhibition of phospholipase Cgamma-1 phosphorylation. Activation of extracellular regulated kinase-2 is also severely impaired. Moreover, at the functional level, interleukin-2 production is abolished. Src homology 2 domain-bearing tyrosine phosphatase SHP-1 and Src homology 2 domain-bearing inositol 5'-phosphatase SHIP usually participate in negative regulation of the BCR. We show that they do not associate with the phosphorylated CD5 chimera. We finally demonstrate that the pseudo-immunoreceptor tyrosine based activation motif present in CD5cyt is involved because its deletion eliminates the inhibitory effect of the chimera, both at biochemical and functional levels. These results demonstrate the inhibitory role of CD5 pseudo-immunoreceptor tyrosine based activation motif tyrosine phosphorylation on BCR signaling. They further support the idea that CD5 uses mechanisms different from those already described to negatively regulate the BCR pathway.

Animals↗
PubMed1995

CD34-positive early stages of human T-cell differentiation.

Thymus, the main organ for T lymphopoiesis, requires a permanent influx of progenitors from bone marrow (BM) or fetal liver. An essential question relating to early T-cell development is the identification of the progenitor population which actually homes to the thymus. Recent findings have shown that human multipotent progenitor/stem cells expressing CD34 have the capacity to differentiate into T cells when introduced into a thymic environment. More mature CD34+ bone marrow cells coexpressing CD7 and having a poor myeloid differentiation capacity can also efficiently differentiate into T cells in vitro. These lymphoid committed precursors might be the true thymic repopulating cells. In the thymus, cells with a similar CD34+7+ phenotype include the most primitive thymocyte precursors. CD34+ thymocytes have no myeloid differentiation potential, but may include precursors for natural killer (NK) cells. Interleukin-7 (IL7) is a potent in vitro growth factor for CD34+ thymocytes. Whereas current data do not support a crucial role for IL2, patients with IL2 receptor gamma chain (IL2R gamma) deficiency lack T- and NK cells. The recent demonstration that IL2R gamma is part of the receptor for IL7 strongly suggests that this cytokine plays an essential role in in vivo T lymphocyte and NK development.

Animals↗
PubMed1992

Interleukin-7 is a growth factor for Sézary lymphoma cells.

Sézary syndrome is a cutaneous T cell lymphoma characterized by infiltration of the skin by CD4+ cells. These cells generally respond poorly to mitogens and T cell activators. We have studied the action of IL1 to IL4, IL6, and IL7 on the proliferation of Sézary cells from 12 patients. With the exception of IL2 and IL7, the cytokines studied had no proliferative effect on these cells. Whereas IL2 had only a low proliferative capacity (two- to threefold increase) on peripheral blood mononuclear cells, recombinant IL7 constantly induced a very significant (3-40-fold increase) proliferative response, and was used successfully to generate cell lines in three out of eight cases. Growth of Sézary cell lines was shown to be strictly dependent on IL7, and after 2-5 wk of culture presented a switch to a homogeneous phenotype CD3+4+8-7- (except for one line that remained CD7+), with a typical morphology of Sézary cells. Their tumoral origin was demonstrated by the expression of the same T cell receptor-beta gene rearrangement as the patients' T cells. Importantly, cultured normal epidermal keratinocyte supernatants could support the growth of our Sézary lines. Furthermore, the proliferative activity contained in these supernatants was completely blocked by a monoclonal anti-IL7 antibody. These results suggest that IL7 may, therefore, represent an important cytokine in the physiopathology of cutaneous T cell lymphoma.

Adult↗
PubMed1992

Effect of CD23 on purified human hematopoietic cells.

We report herein the effect of soluble CD23 (sCD23) on the differentiation of lymphoid and myeloid precursors. CD23 is known as the low affinity receptor for IgE. In addition to it, our results indicate that sCD23 in synergy with IL1 is able to promote the maturation of normal and leukemic hematopoietic progenitor cells.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1991

The differentiation of human pro-thymocytes along the TCR-alpha/beta pathway in vitro is accompanied by the site-specific deletion of the TCR-delta locus.

The nested location of the TCR-delta gene within the TCR-alpha locus is a common feature of both mouse and human. Yet alpha/beta and gamma/delta T cells represent two separate lineages. We have previously proposed that a specific rearrangement event (delta Rec--psi J alpha) resulting in the specific deletion of the TCR-delta gene could be responsible for the independent usage of these two loci. We used an in vitro model of T cell differentiation to test this hypothesis. We show that in culture conditions (IL-1 + sCD23) which promote the development of alpha/beta expressing T cells exclusively, the specific deletion of the TCR-delta locus occurs very rapidly, probably before the productive rearrangement of the TCR-alpha gene. These results clearly demonstrate that the specific deletion of the TCR-delta gene could be the initial regulatory event that imprints the irreversible commitment of T cell differentiation along the alpha/beta pathway.

Base Sequence↗