Chronic myeloid leukemia (CML) is characterized by an initial chronic phase of expanded yet orderly clonal hematopoiesis that is distinguished by the BCR-ABL gene rearrangement. We found that although the mature myeloid compartment in patients with CML was expanded and entirely derived from the dominant leukemic clone, the primitive hematopoietic progenitor compartment did not show a corresponding expansion and was substantially enriched for cells without the BCR-ABL gene rearrangement. More importantly, primitive progenitors exhibiting the BCR-ABL gene rearrangement did not express either the BCR-ABL hybrid mRNA or fusion protein (P210). Expression of P210 protein and BCR-ABL mRNA increased with myeloid commitment in vivo as well as with growth factor-induced proliferation and differentiation of the primitive CML progenitors in vitro. This differential expression of BCR- ABL between primitive and mature CML progenitors may explain the expansion of the leukemic clone at the level of mature myeloid progenitors and granulocytes without a concomitant expansion of primitive CML progenitors. Because BCR-ABL mRNA is minimally expressed or may be absent in primitive CML progenitors, these cells may escape detection by reverse transcriptase-polymerase chain reaction and eradication by antisense oligonucleotides targeted against BCR-ABL mRNA.