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...

We investigated the expression of the PLZF gene in purified human hematopoietic progenitors induced to unilineage erythroid, granulocytic or megakaryocytic differentiation and maturation in serum-free culture. PLZF is expressed in quiescent progenitors: the expression level progressively rises through megakaryocytic development, whereas it gradually declines in erythroid and granulopoietic culture. To investigate the role of PLZF in megakaryopoiesis, we transduced the PLZF gene into the erythro-megakaryocytic TF1 cell line. PLZF overexpression upmodulates the megakaryocytic specific markers (CD42a, CD42b, CD61, PF4) and induces the thrombopoietin receptor (TpoR). The proximal promoter of the TpoR gene is activated in PLZF-expressing TF1 cells: in this promoter region, a PLZF DNA-binding site was identified by deletion constructs studies. Interestingly, PLZF and GATA1 proteins coimmunoprecipitate in PLZF-expressing TF1 cells: enforced expression of both PLZF and GATA1 in TF1 cells results in increased upregulation of megakaryocytic markers, as compared to exogenous PLZF or GATA1 alone, suggesting a functional role for the PLZF/GATA1 complex. Our data indicate that PLZF plays a significant stimulatory role in megakaryocytic development, seemingly mediated in part by induction of TpoR expression at transcriptional level. This stimulatory effect is potentiated by physical interaction of PLZF and GATA1, which are possibly assembled in a multiprotein transcriptional complex.