We have investigated the expression of interleukin-3 receptor ␣ (IL-3R␣) chain in primary blasts from 79 patients with acute myeloid leukemia (AML), 25 patients with B-acute lymphoid leukemia (B-ALL), and 7 patients with T-acute lymphoid leukemia (T-ALL) to evaluate a linkage between the expression of this receptor chain, blast proliferative status, and disease prognosis. Although IL-3R␣ chain was scarcely expressed in most patients with T-ALL, it was overexpressed in 40% and 45% of patients with B-ALL and AML, respectively, compared with the levels observed in normal CD34 ؉ progenitors. The biological and clinical significance of this overexpression pattern was investigated in AML. At the biological level, elevated IL-3R␣ expression was associated with peculiar properties of leukemic blasts, specifically in 3 areas. First, in all patients the blasts expressing elevated IL-3R␣ levels exhibited higher cycling activity and increased resistance to apoptosis triggered by growth factor deprivation. Second, spontaneous signal transducer and activator of transcription 5 (Stat5) phosphorylation was observed in 13% of AML patients, all pertaining to the group of patients exhibiting high IL-3R␣ expression. Third, following IL-3 treatment, Stat5 was activated at higher levels in blasts with elevated IL-3R␣ expression. At the clinical level, a significant correlation was observed between the level of IL-3R␣ expression and the number of leukemic blasts at diagnosis, and patients exhibiting elevated IL-3R␣ levels had a lower complete remission rate and survival duration than those showing normal IL-3R␣ levels. These findings suggest that in AML, deregulated expression of IL-3R␣ may contribute to the proliferative advantage of the leukemic blasts and, hence, to a poor prognosis. IntroductionBlood cells are derived from a small number of pluripotent hemopoietic stem cells (HSCs) endowed with the capacity to self-renew and to differentiate into hemopoietic progenitor cells (HPCs) progressively committed to proceed along one of the maturation pathways. 1 Survival, growth, and differentiation of HPCs are, at least in part, regulated by a network of hematopoietic growth factors (HGFs) called colony-stimulating factors (CSFs) or interleukins (ILs).Acute leukemias are characterized by an arrest of cell maturation and the accumulation of undifferentiated cells in marrow, blood, and other tissues. 2 As observed in normal hematopoiesis, most leukemic cells descend from a relatively small pool of progenitor cells with high proliferative activity. In line with this hypothesis, recent studies have shown that acute myeloid leukemia (AML) cells with the membrane phenotype CD34 ϩ Thy-1 Ϫ , 3 CD34 ϩ CD38 Ϫ , 4 or CD34 ϩ CD71 Ϫ HLA-DR Ϫ5 are capable of engrafting immunodeficient mice.Acute leukemia cells have usually retained responsiveness to HGF stimulation in the promotion of cell survival and cell proliferation; however, leukemic cells show little maturation under stimulation with HGFs. 6 More particularly, recombinant IL-3 and granulocyte...
IntroductionDuring megakaryocytic (Mk) differentiation, Mk precursors switch from a mitotic to an endomitotic process characterized by DNA duplication without cytokinesis. This still poorly understood process leads to the formation of large polyploid cells with polylobulated nuclei that, in turn, give rise to platelets by cytoplasm fragmentation. 1,2 The major regulator of Mk development, Mpl ligand/ thrombopoietin (TPO), acts at all stages of megakaryocytopoiesis: commitment and proliferation of hematopoietic progenitor cells (HPCs), polyploidization of Mk precursors, and final maturation, including the formation of membrane demarcations and platelet production (reviewed in Kaushansky, 1 ZuckerFranklin and Kaushansky, 2 Zimmet and Ravid, 3 Cramer et al 4 ). However, despite these properties, TPO fails to induce in vitro a level of Mk polyploidization comparable to that observed in vivo. 5-7 Addition of either single or combined cytokines (ie, kit ligand, interleukin-3, interleukin-6) to TPO-containing cultures, although improving Mk proliferation, negatively affects cytoplasmic maturation and polyploidization. 5,6 Similarly, although erythropoietin (Epo) is considered the main growth factor stimulating erythropoiesis, additional cytokines are required at early and late erythroid (E) stages. 8 Vascular endothelial growth factor (VEGF) is a key factor for proliferation and survival of endothelial cells. [9][10][11] The VEGF family, including VEGF/VEGF-A, -B, -C, -D, and -E, 10-12 as well as the placenta growth factor (PlGF), 13 mediates angiogenic signals to endothelial cells through the binding with tyrosine kinase receptors designated VEGFR-1/Flt1, VEGFR-2/KDR/Flk1, and VEGFR-3/Flt-4. 14 VEGF is the ligand of both Flt1 and kinase domain receptor (KDR) and consists of several isoforms generated by alternative splicing of a single mRNA precursor (VEGF121, 145, 165, 189, or 206), which differ in their molecular mass and their biologic properties, such as the ability to bind heparin or heparinlike molecules on cell surface. 10,15 VEGF expression is enhanced spatially and temporally and is associated with physiologic events leading to angiogenesis in vivo, and its production is potentiated by hypoxia. 16 Studies on gene knockout mice demonstrated the physiologic role of VEGF and its receptors, as central regulators of the development of vascular and hemopoietic tissues. Flt1 knockout causes a selective defect in the assembly and organization of vasculature. 17 Lack of either VEGF or KDR gene causes major defects in both vasculogenesis and blood island formation, 18-21 suggesting the existence in embryonic life of a bipotent stem cell (SC) for hematopoietic and endothelial lineages, the hemangioblast.In postnatal life, both Flt1 and KDR are expressed at low levels on CD34 ϩ HPCs. [22][23][24][25][26][27] More important, the small fraction of CD34 ϩ Materials and methods Hematopoietic growth factors (HGFs) and culture mediaRecombinant human interleukin 3 (rhIL-3), granulomonocytic colony-stimulating factor (rhGM-C...
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