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.

We report three novel adenosine deaminase (ADA) mutations with interesting implications. A Somali child with severe combined immunodeficiency disease (SCID) had reduced ADA mRNA in T cells and was homozygous for the nonsense mutation Q3X. Unexpectedly, her healthy father was a compound ADA heterozygote whose second allele carried a 'partial' mutation, R142Q, due to a G-->A transition of a CpG dinucleotide. A C-->T transition of the same CpG produced a nonsense mutation, R142X, in two homozygous Canadian Mennonite infants with SCID. The severe and healthy phenotypes associated with R142X and R142Q, the high frequency of 'partial' ADA mutations arising from CpGs in healthy individuals of African descent and the presence of CAA (glutamine) at codon 142 in murine ADA, suggest selection for replacement of this CpG hotspot by CpA during ADA evolution. R142X, located within a purine-rich segment at nt 62/116 of exon 5, caused skipping of the exon, possibly by disrupting a splicing enhancer. Absence of exon 5 in T cell ADA mRNA and low ADA activity in T cells and erythrocytes obtained at age 18-22 months from one of the Mennonite children, indicate limited expression of a normal ADA cDNA from retrovirally transduced CD34+ umbilical cord leukocytes infused shortly after birth in an attempt at stem cell gene therapy.