Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Despite the progress achieved in its treatment, 20% of cases relapse and no longer respond to chemotherapy. The most common phenotype of ALL cells share surface antigens with very early precursors of B cells and are therefore believed to originate from this lineage. Characterization of the growth requirement of ALL cells indicated that they were dependent on various cytokines, suggesting paracrine and/or autocrine growth regulation. Because many cytokines induce tyrosine phosphorylation in lymphoid progenitor cells, and constitutive tyrosine phosphorylation is commonly observed in B-lineage leukaemias, attempts have been made to develop protein tyrosine kinase (PTK) blockers of leukaemia cell growth. Here we show that leukaemic cells from patients in relapse have constitutively activated Jak-2 PTK. Inhibition of Jak-2 activity by a specific tyrosine kinase blocker, AG-490, selectively blocks leukaemic cell growth in vitro and in vivo by inducing programmed cell death, with no deleterious effect on normal haematopoiesis.

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Profound cellular immunodeficiency occurs as the result of mutations in proteins involved in both the differentiation and function of mature lymphoid cells. We describe here a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor ␣ chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin 2. This immunodeficiency is characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development. Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inf lammation. Although mature T cells are present, the absence of CD25 does affect the differentiation of thymocytes. While displaying normal development of CD2, CD3, CD4, and CD8 expression, CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2.The high-affinity receptor for interleukin 2 (IL-2) (1) is composed of three subunits: ␣ (CD25), ␤ (CD122), and ␥ (␥ common ). While the ␤ and ␥ chains are constitutively expressed upon T lymphocytes, ␣ expression is restricted to the early stages of thymocyte development and to activated mature T lymphocytes. Although the ␤ and ␥ chains together can form an IL-2 receptor (IL-2R) of low affinity, the ␣ chain cannot form a functional receptor in the absence of the others (1). The presence of the high-affinity receptor upon activated peripheral T cells is believed to be necessary for optimal proliferative responses to IL-2 after stimulation of the T cell antigen receptor; however the role of the ␣␤␥ complex upon triplenegative thymocytes is less certain.Deletion of the IL-2R ␥ chain in humans results in the development of severe combined immunodeficiency (2) (Xlinked) characterized by a great reduction in, or absence of, peripheral T lymphocytes (3), due to the participation of the ␥ chain in multiple cytokine receptor complexes (i.e., with interleukins 2, 4, 7, 9, and 15). In mice, B cell development is also ablated (4). In sharp contrast, the absence of CD122 manifests in the constitutive activation of B and T lymphocytes accompanied by the development of autoimmune responses resulting in premature death (5). The absence of CD25 in mice would appear to cause the least severe impairment of the three. Young CD25-null mice have phenotypically normal T and B cell populations, while older animals exhibit enlarged lymphoid glands due to increased B and T cell populations (as the result of inefficient activation-induced cell death) and a propensity to develop autoimmune disorders (6).We describe here a human mutation of CD25 ablating its expression and the consequences upon immune function. Analysis of this patient suggests that expression of the IL-2R ␣ chain is necessary not only in the functional responses of mature T cells but also in preventing the generation and͞or controlling of autoreactive T lymphocytes. MATERIALS AND METHODSTissue Section Pr...