Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. We report that somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis. All mutations were missense, and some were predicted to destabilize interdomain interactions controlling the activity of the kinase. Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3–independent growth in Ba/F3 cells and/or IL-9–independent resistance to dexamethasone-induced apoptosis in T cell lymphoma BW5147 cells. Such effects were associated with variably enhanced activation of multiple downstream signaling pathways. Leukemic cells with mutated JAK1 alleles shared a gene expression signature characterized by transcriptional up-regulation of genes positively controlled by JAK signaling. Our findings implicate dysregulated JAK1 function in ALL, particularly of T cell origin, and point to this kinase as a target for the development of novel antileukemic drugs.

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...