We studied the relationship of direct karyotypes, determined at diagnosis and 
remission, to Abelson-related tyrosine kinase activity and the cytogenetic 
features of erythroid and myeloid colonies derived from remission marrow of six 
children with acute lymphoblastic leukemia (ALL). These patients had either the 
characteristic Philadelphia chromosome (Ph1) [t(9;22)(q34;q11)] or 
cytogenetically similar variants with a 22q11 breakpoint but no detectable 
cytogenetic involvement of 9q34. The findings suggested two distinct subtypes of 
ALL: one defined by t(9;22)(q34;q11) and expression of P185BCR-ABL tyrosine 
kinase and one with variant karyotypes and no P185BCR-ABL expression. The former 
comprises cases with Ph1 + marrow cells and Ph1 + erythroid and (or) myeloid 
colonies in remission marrow and others in which the t(9;22) is undetectable in 
remission marrow cells. In the latter subgroup, the disease may reflect more 
extreme mosaicism with a similar stem cell that is cytogenetically undetectable. 
Variant karyotypes included a del(22)(q11) in one patient and a t(6;22;15;9) 
(q21;q11;q?22;q21) in another; in both instances, the malignant blast cells 
lacked P185BCR-ABL expression. Thus ALL with t(9;22)(q34;q11) should be 
distinguished from ALL with other involvement of the 22q11 breakpoint by 
molecular studies including protein expression. The diversity of karyotypic 
findings in cases with involvement of 22q11 suggests at least two mechanisms of 
leukemogenesis in patients with ALL defined by this breakpoint.