Abstract SY39-03: Stem cell competition is central to leukemogenesis

Abstract

Abstract Tissue stem cells regenerate the body and are the only cells that maintain self-renewal throughout life. When stem cells divide they give rise to stem cells (by self-renewal) and progenitors (by differentiation). Stem cell isolation and transplantation is the basis for regenerative medicine. We isolated mouse and then human hematopoietic stem cells (HSCs). Importantly, we demonstrated that transplantation of purified HSCs results in complete regeneration of the blood and immune systems without causing graft vs. host disease, and can induce permanent transplant tolerance of any organ or cell from the HSC donor. In a clinical trial in metastatic breast cancer patients, HSC purification made autologous transplantation to cancer patients possible, without including cancerous cells in the graft. The 15-year overall survival rate was ~7% in recipients of mobilized peripheral blood (MPB) autologous transplantation, and ~33% in recipients of cancer-free HSCs. We have also prospectively isolated human fetal brain CNS stem cells and found a method to propagate them without changing phenotype or normal regenerative functions upon transplantation. These are and have been used in clinical trials with children with genetic neurodegenerative diseases such as Batten and Pelizeus Mehrbacher, in patients with thoracic and cervical spinal cord injuries, and in patients with age-related macular degeneration. Self-renewal is strictly regulated and restricted to stem cells, because deregulation can lead to cancer. To study the relationship between stem cells and cancer, we followed the progression from hematopoietic stem cells (HSCs) to myelogenous leukemias. We found that the developing precancerous clones progress and accumulate mutations at the stage of HSCs, until they become fully malignant. At this point, the “leukemia” stem cell is a downstream oligolineage or multilineage progenitor that has evaded programmed cell death and programmed cell removal, and also acquired self-renewal. In the case of chronic myeloid leukemia (CML), bcr-abl+ HSC clones outcompete normal HSCs in the chronic phase. The transition from CML to myeloid blast crisis results in the leukemia stem cells appearing in the granulocyte-macrophage progenitor (GMP) stage, and is accompanied by cell intrinsic activation of β-catenin, endowing the already mutant progenitors with a self-renewal capacity. While there are many ways to defeat programmed cell death and senescence, there appears to be one dominant method that cancer cells use to avoid programmed cell removal—the elevated expression of the cell surface “don't eat me” protein CD47, the ligand for macrophage SIRPα. All cancers tested express CD47 to overcome expression of “eat me” signals such as calreticulin that is produced by macrophages and adheres to asialogylycoproteins on the surface of cancer cells. Antibodies that block the CD47-SIRPα interaction enable phagocytosis and killing of the tumor cells in vitro and in vivo. This includes human solid tumors and lymphomas/leukemias/myelomas. We showed that anti-CD47 antibodies or high-affinity SIRPα proteins synergize with anti-CD20 antibodies to eliminate human non-Hodgkin lymphoma in immune-deficient mice. We generated a humanized antibody of the IgG4 isotype, and these compounds are currently being tested in clinical trials. Citation Format: Irving L. Weissman. Stem cell competition is central to leukemogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY39-03.