Acute lymphocytic leukemia (ALL) is considered a clonal disease restricted to the lymphoid compartment. The Philadelphia chromosome (Ph) is found in a subset of ALL with poor prognosis. Here we present the largest series of Ph+ ALL analyzed for involvement of the myeloid compartment. For the first time at a single cell level the presence of Ph in lineages other than lymphoid is demonstrated. Granulocytes from nine patients diagnosed with BCR-ABL + ALL (eight Ph+, one Ph-) were purified using two layer density gradient separation. They were further identified by the morphology of DAPI-stained nuclei and studied for the presence of the Ph by fluorescence in situ hybridization (FISH) using a BCR-ABL dual-color probe. Ph was demonstrated in 30 to 93% of granulocytes in all patients. FISH identified major and minor BCR gene breakpoints (M-bcr and m-bcr). In one patient, with CD19+/34+/33-/2-/3-/7-/10- lymphoblasts, involvement of B cells (CD19+), T cells (CD3+), myeloid (CD13+), erythroid (glycophorin A+) cells was found by FISH following fluorescence-activated cell sorting (FACS). The diagnosis of ALL as opposed to lymphoblastic transformation of CML was established based on clinical and laboratory data including Western blot results demonstrating the presence of p190/m-bcr in five of the nine cases studied. Results suggest that Ph+ ALL originates from a pluripotent stem cell.