Characterization and selection of benign stem cells in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a clonal disorder arising from the hematopoietic stem cell, characterized by the Philadelphia chromosome (Ph) and, at the molecular level, by fusion of the BCR (breakpoint cluster region) gene and the c-ABL gene. The hallmark of CML is represented by a marked increase in the number of leukemic progenitors, as well as more mature cells, in the bone marrow (BM) and peripheral blood (PB). Despite expansion of the leukemic clone, normal Ph-negative stem cells have been demonstrated to survive in CML. Early observations of partial, but transient, restoration of Ph-negative hematopoiesis after high-dose chemotherapy have recently been extended by the use of myeloablative regimens followed by autografting with marrow or blood-derived stem cells. Moreover, treatment of early-stage CML patients with the biologic response modifier alpha-interferon (alpha-IFN) has led to the re-emergence of normal progenitor cells. Concurrently, "in-vitro" studies have reported that cultures of CML marrow in the presence of a stromal feeder-layer resulted in depletion of Ph-positive cells and predominance of Ph-negative hematopoietic precursors. Based on the assumption that normal and malignant stem cells may coexist in CML, several studies have recently been directed toward the characterization and "in-vitro" selection of benign progenitors within CML hematopoiesis. The results of those studies demonstrated that normal precursors can be phenotypically and functionally identified in the BM or PB of Ph-positive CML patients. These cells are included in the earliest identifiable hematopoietic cell compartment. Normal cells do not bear cell surface lymphoid or myeloid-lineage antigens, express high levels of the CD34 antigen, and fail to express the HLA-DR antigen. Furthermore, they possess a great capacity for adhering to marrow stroma. This cell population represents only a small minority of hematopoietic progenitors, but it retains many of the properties associated with putative hematopoietic stem cells. Thus, purification of a population of benign hematopoietic precursors that could be used for autologous bone marrow transplantation (ABMT) may be feasible in CML patients.