Clonal nature of hematopoietic stem cell disorders.

In a paper published in the present issue of Haema-tologica, 1 Guidetti et al. investigate the clonal origin of hematopoietic cells in patients with myelodysplastic syndromes (MDS). Several cell populations were analyzed , including peripheral blood granulocytes and T lymphocytes, bone marrow hematopoietic progenitors (CFU-GM and BFU-E) and long-term culture-initiating cells (LTC-IC), which represent the most immature human hematopoietic cells that can be isolated and cultured in vitro. It was was established that these cell populations were clonal through analysis of the X-chromosome inactivation pattern in female patients. This assay is based on the random inactivation of one X-chromosome in female cells. Such inactivation occurs early during embryogenesis, probably at a stage when fewer than 20 precursors of hematopoietic stem cells are present, 2 and the progeny of a single cell shows inactivation of the same parental chromosome X as the common progenitor cell. The consequence is that if tumors derive from the neoplastic transformation of a single cell, the same chromosome X would be inactivated in each tumor cell. X-chromosome inactivation studies have been used to investigate the clonal nature of several disease entities , 3-5 the multistep pathogenesis of MDS, 6 the involvement of different cell lineages in hematologic malig-nancies, 7,8 and to show the polyclonal nature of complete remissions following aggressive chemotherapy in acute (AML) and chronic (CML) myeloid leukemias. The results reported by Guidetti et al. show that whereas granulocytes, CFU-GM and BFU-E are clonal in MDS patients, more immature LTC-IC are polyclon-al. Although these data were obtained in a small group of MDS patients, they not only confirm results of previous works indicating that polyclonal hemopoietic stem cells are still present in some MDS patients who obtain hematologic remissions following chemothera-py, 11 but further suggest that some, perhaps most, residual stem cells in MDS are polyclonal in origin and do not belong to the dysplastic clone. In vivo, however, such polyclonal stem cells do not give origin to an adequate progeny of differentiated cells because they are suppressed by the clonal, dysplastic cell population. Similar observations had already been made in patients with CML by Frassoni et al. 12 who found that during the early phases of CML most LTC-IC are Philadelphia negative. Since it is generally accepted that Philadelphia negative cells in CML are polyclonal, it now appears that a relatively large population of normal stem cells persists in several hemopoietic malignancies, such as …