Discordant maturation as the primary biological defect in chronic myelogenous leukemia

Comparative studies of the in vitro growth characteristics of normal and chronic myelogenous leukemic (CML) progenitor cells have provided further evidence that discordant maturation is the primary biological defect in CML. The in vitro growth of total normal and CML granulocyte/macrophage colony forming unit (CFU-GM) populations were compared with early and intermediate (HLA-DR positive) CFU-GM derived from the same marrows. The absolute number of total CML CFU-GM exceeded the number generated by normal marrow through 7 days of culture due entirely to an excess of CML CFU-GM with limited proliferative capacity. Unlike normal colonies, relatively few of the leukemic colonies grew to a large size; the early and intermediate (HLA-DR positive) CML progenitors also exhibited limited proliferative capacity compared to normal. Highly enriched progenitor populations were prepared, and it was observed that the primitive (small) CML CFU-GM also had greatly reduced proliferative potential compared to primitive normal progenitors, but rather behaved similarly to normal mature (large) CFU-GM. Similarly, CML erythroid burst forming units were at a more advanced stage of maturation than normal erythroid burst forming units as evidenced by their reduced proliferative capacity, the observation that a reduced proportion required burst promoting activity to enable them to respond to erythropoietin and the observation that a larger fraction than normal could sustain a limited period of erythropoietin deprivation in the absence of burst promoting activity. Based on these findings and supporting evidence from our previous studies and those reported by other investigators, it is concluded that the dominance of the leukemic population is not due to unregulated proliferation but rather to discordant maturation resulting in expansion in the later maturational compartments which are not under strict regulatory control.