Biology of chronic myelogenous leukemia: Is discordant maturation the primary defect?

In summary, the significant differences we have observed between comparable chronic phase CML and normal marrow progenitor populations are as follows: 1. 1. Relative to normal, CML core bone marrow biopsies produced progressively fewer immature myeloid cells but this was balanced by an increased production of more mature myeloid cells (Table 1).^32,73 2. 2. The elevated numbers of CFU-GM aggregates in CML marrow, at three to seven days in culture, appeared to be derived from HLA-DR negative mature promyelocytes and myelocytes with very limited proliferative capacity because no increased number was seen in HLA-DR positive populations; ^74a (Table 2). 3. 3. At all culture time (three to 21 days), ≥ 74% of the total GM colonies from CML marrow were derived from large (mature) CFU-GM. In contrast, the contribution of normal mature CFU-GM to the total GM colonies present decreased with time concomitant with an increased contribution by normal small (primitive) CFU-GM (Table 3).⁷³ 4. 4. CML marrows did not have increased numbers of small (primitive) CFU-GM but rather had increased numbers of large (mature) CFU-GM, and this mature population of CFU-GM was responsible for the increased number of GM aggregates in CML marrow through ten days of culture (Table 4).⁷³ 5. 5. The growth patterns of highly enriched populations of CML primitive (small) and normal mature (large) blast populations were similar and both differed significantly in their proliferative potential when compared to normal primitive blast populations (Table 5). The observations cited above strongly suggest that the most mature proliferating cells (ie, late blasts, late promyelocytes, and myelocytes) are mainly responsible for the expansion of the Ph¹-positive population. The experimental systems do not permit one to determine how many divisions normal or Ph¹-positive cells undergo during their sojourns in each progressive maturational compartment, but the evidence cited indicates that the most mature proliferating CML cells are undergoing slightly more divisions than comparable normal mature proliferating cells. 6. 6. Highly enriched normal primitive blast progenitor populations contained only a minor population of CFU-GM that could begin to divide to a limited degree in the absence of CSF with no additional augmentation by rGM-CSF and rhG-CSF, and 70% or more could generate large GM colonies in the presence of MoCM. In contrast, the majority of CML primitive CFU-GM (from comparable populations), could begin to divide to a limited degree in the absence of CSF, responded well to rGM-CSF and rhG-CSF, but only 15% could generate large GM colonies in the presence of MoCM. Normal mature CFU-GM behaved similarly to CML primitive CFU-GM, suggesting that the behavior of CML primitive progenitors resembles the behavior of normal mature progenitors, which is compatible with the observation that CML marrows have increased numbers of mature CFU-GM but no increased numbers of primitive CFU-GM; ^74a (Tables 3-6). 7. 7. Relative to normal, very few CML primitive BFU-E required BPA for development, and a significantly greater proportion of all CML BFU-E could sustain 48 hours of EPO deprivtion, most likely due to an increase in EPO-receptor complexes; ^74a (Table 7). 8. 8. CML marrow CFU-GM, BFU-E, and CFU-GEM, derived from light density cells, HLA-DR positive cells, and highly enriched primitive and mature blast populations, had a markedly reduced proliferative capacity relative to comparable normal populations. ^73,74a 9. 9. CML myeloblasts, promyelocytes, and myelocytes have lower mitotic and ³H · TdR LIs than comparable normal granulocyte precursors,⁶² indicating that increased granulocyte production in CML is not due to an increased proliferative rate of precursor cells. 10. 10. The presence of Ph¹-negative progenitors could be detected in the small (primitive) progenitor population in some patients with 100% Ph¹-positive metaphases on direct marrow cytogenetic analysis due to the decreased proliferative potential of Ph¹-positive small (primitive) progenitor cells.³² The inability to detect Ph¹-negative mature progenitors is due to the expansion of mature Ph¹-positive progenitors, which obscures a minor Ph¹-negative population.