A primitive hematopoietic cell is the target for the leukemic transformation in human Philadelphia-positive acute lymphoblastic leukemia

BCR-ABL is a chimeric oncogene generated by translocation of sequences from the chromosomal counterpart (c-ABL gene) on chromosome 9 into the BCR gene on chromosome 22, Alternative chimeric proteins, BCR.ABLp(190) and BCRABLp (210), are produced that are characteristic of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (P h-1-ALL). In CML, the transformation occurs at the level of pluripotent ste m cells, However, Ph-1-ALL is thought to affect progenitor cells with lymph oid differentiation. Here we demonstrate that the cell capable of initiatin g human Ph-1-ALL in non-obese diabetic mice with severe combined immunodefi ciency disease (NOD/SCID), termed SCID leukemia-initiating cell (SL-IC), po ssesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell, The SL-ICs from all Ph-1 -ALL analyzed, regardless of the het-erogeneity in maturation characteristi cs of the leukemic blasts, were exclusively CD34(+) CD38(-), which is simil ar to the cell-surface phenotype of normal SCID-repopulating cells. This in dicates that normal primitive cells, rather than committed progenitor cells , are the target for leukemic transformation in Ph-1-ALL. (C) 2000 by The American Society of Hematology.