Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for cancer clone maintenance and propagation. Here we have examined this issue in childhood acute lymphoblastic leukaemia in which the ETV6-RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or 'driver' copy number alterations. By multiplexing fluorescence in situ hybridization probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of subclones identified and a composite picture of subclonal architecture and putative ancestral trees assembled. Subclones in acute lymphoblastic leukaemia have variegated genetics and complex, nonlinear or branching evolutionary histories. Copy number alterations are independently and reiteratively acquired in subclones of individual patients, and in no preferential order. Clonal architecture is dynamic and is subject to change in the lead-up to a diagnosis and in relapse. Leukaemia propagating cells, assayed by serial transplantation in NOD/SCID IL2Rγ(null) mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive regenerative capacity in vivo. These data have implications for cancer genomics and for the targeted therapy of cancer.

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We describe the clinical and laboratory findings of 78 adult patients with T-prolymphocytic leukemia (T-PLL) studied over the last 12 years. The main disease features were splenomegaly (73%), lymphadenopathy (53%), hepatomegaly (40%), skin lesions (27%), and a high leukocyte count (greater than 100 x 10(9)/L in 75%) with nucleolated prolymphocytes. A variant form with small, less typical cells was recognized in 19%. Membrane markers defined a postthymic phenotype TdT- , CD2+, CD3+, CD5+, CD7+; in 65%, the cells were CD4+ CD8-, in 21%, they coexpressed CD4 and CD8, and, in 13%, they were CD4- CD8+. Serology for human T-cell leukemia/lymphoma virus Type-I (HTLV-I) was negative in the 27 cases investigated. Cytogenetic analysis in 30 cases showed a consistent abnormality of chromosome 14, usually inv (14), with breakpoints at q11 and q32 in 76% of cases. Trisomy 8, including iso8q, was shown in 53%; t (11;14)(q13;q32) was documented in one case; and one had a normal karyotype. The clinical course was progressive with a median survival of 7.5 months. Thirty-one patients were treated with 2′ deoxycoformycin and 15 responded (3 complete remissions and 12 partial remissions); the response rate (48%) increased to 58% in patients with a CD4+ CD8- phenotype. The median survival of responders was 16 months and of nonresponders 10 months; other treatments were less effective. T-PLL is a distinct clinico-pathologic entity with aggressive course and characteristic chromosome abnormalities. A subgroup of patients may benefit from deoxycoformycin.