Theoretical Basis for HCST in AML
Sustained leukemia-free survival is achieved in less than a third of nonelderly patients with AML treated with conventional chemotherapy, despite the achievement of complete remission in most. Results in patients 60 years and older are dismal, with cure rates under 5%. The chemotherapy used to treat cancers, including AML, is most effective in killing proliferating cells. The bulk of an individual's leukemic cells can usually be eliminated with standard chemotherapy, thereby achieving remission. However, leukemic stem cells, which appear to be responsible for the initiation and sustenance of leukemia, are insensitive to standard chemotherapy. As is the case for normal hematopoietic stem cells, whose resistance to chemotherapy is essential for recovery of blood counts and survival after chemotherapy, malignant stem cells are quiescent, excrete toxic drugs by ATP-binding transporters, repair DNA efficiently and resist apoptosis. These characteristics protect leukemic and normal hematopoietic stem cells from standard chemotherapy. Cure of leukemia would seem to require the eradication of these rare leukemic stem cells from which the disease originates. When malignant stem cells are analyzed by their capacity to initiate and sustain human leukemia in immunologically susceptible mice, a model in which demands on stem cells are less stringent than in humans, only one in 10,000 to one in a million leukemic blasts appears to be a true malignant stem cell. Standard chemotherapy may eliminate the bulk of tumor cells, but appears to leave leukemic stem cells unscathed. These cells can be responsible for later relapse.
Mature hematologic cells are produced and replenished by progenitor cells, which are derived from hematopoietic stem cells. All stem cells possess the unique ability to self-renew, retaining the capacity for unlimited division and maintaining a source of blood cells for life. The sustained and complete restoration of lymphohematopoiesis in a lethally irradiated animal by a single hematopoietic stem cell provides evidence of its capacity for multipotency and self-renewal. Leukemic stem cells result from mutations of normal hematopoietic stem cells or through mutations in progenitor cells that confer the ability to self-renew.[5,6,7]
In allogeneic transplantation, myeloablative doses of radiation plus chemotherapy in combination with the immunologic effect of donor cells appear capable of eliminating human AML stem cells in addition to the bulk of leukemic cells. Cytotoxic T-lymphocyte clones from the donor may eliminate human AML stem cells along with other leukemic cells on the basis of minor histocompatibility antigens ‘mismatched' between donor and recipient (Figure 1),[9,10,11,12] or aberrantly expressed proteins on leukemic cells.[13,14]
Graft-versus-leukemia effect from a minor histocompatibility antigen. A protein encoded by a Y-chromosome gene of a male graft recipient is degraded within the proteasome. A peptide derived from the polymorphic protein is then transported to the endoplasmic reticulum, where it binds an HLA glycoprotein encoded by one of the HLA complex genes on chromosome 6 (the HLA loci important in matching are shown). The HLA glycoprotein (here, class I) and bound peptide travel through the Golgi apparatus to the cell surface, where the peptide is recognized as foreign by a T cell from the female donor. The class I gene encodes the α-polypeptide chain, which includes the α1 and α2 peptide-binding domains and the α3 immunoglobulin-like domain, the transmembrane region and the cytoplasmic tail. The β2-microglobulin is encoded by a gene on chromosome 15 (not shown). Minor histocompatibility antigens selectively expressed on hematopoietic cells cause a graft-versus-leukemia effect, but not graft-versus-host disease; antigens expressed on hematopoietic cells and epithelial cells cause both.
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Future Oncol. 2009;5(4):559-568. © 2009 Future Medicine Ltd.
Cite this: Treatment of Acute Myeloid Leukemia With Hematopoietic Stem Cell Transplantation - Medscape - May 01, 2009.