Acute lymphoblastic leukemia (ALL) with a high hyperdiploid clone has a good prognosis for both childhood and adult patients while patients with Philadelphia-positive (Ph) ALL do badly at all age groups. It has been suggested that different responses to treatment might be related to the cell of origin of the leukemia with 'stem cell' cases responding less well than those arising in a lymphoid committed progenitor cell. The clonal involvement of different cell lineages in 12 patients with acute lymphoblastic leukemia has been examined by applying fluorescence in situ hybridization (FISH) to detect chromosomal abnormalities in bone marrow cells previously identified by morphology and/or immunology. The karyotype of the malignant clone was either high hyperdiploid or Philadelphia translocation (Ph) positive with a breakpoint in the minor breakpoint cluster region of the BCRgene (m-BCR) or in the major breakpoint cluster region of the BCR gene (M-BCR). The high hyperdiploid clone, in each case, was found in cells of the B-lymphoid (CD19+) lineage but not in T cells (CD3+) or in cells of the myeloid (CD13+) or erythroid (glycophorin A+) lineages, indicative of a lymphoid committed progenitor cell. Heterogeneity of lineage involvement was found in Ph+ ALL: the m-BCR Ph+ clone was found in lymphoid/blast cells but not in neutrophils or eosinophils. In contrast both M-BCR Ph+ clones were detected in myeloid as well as lymphoid lineages, indicative of a stem cell origin.