The myeloproliferative disorders result from the neoplastic transformation then clonal expansion of a single hematopoietic stem cell (HSC). The interactions of normal and neoplastic HSC are poorly understood, yet are the key to understanding disease progression. Some argue that neoplastic cells actively suppress normal hematopoiesis through toxic or immunologic mechanisms, although experimental evidence is lacking. Clearly, neoplastic HSC increase in number and are capable of survival at geographic sites (i.e., liver and spleen) that cannot support normal adult blood cell development. This has lead to the presumption that myeloproliferative HSC ignore the environmental cues that control HSC compartment size and maintain homeostasis. Our goal is to test this hypothesis. HSC are infrequent (1 to 10 per 10[5] nucleated marrow cells in mouse, likely < 1 per 10[7] nucleated marrow cells in man), reside in geographically separate regions of the marrow space, and are dependent on extrinsic (microenvironmental), as well as intrinsic, cues for fate decisions. Therefore, the in vivo behavior of HSC cannot be observed directly, but rather must be inferred from observations of the behavior of derivative cell populations. This difficulty in defining and observing HSC provides a significant obstacle to understanding the clonal progression of the myeloproliferative disorders. Previously, we have estimated the replication, differentiation, and apoptosis rates of murine and feline HSC in vivo by stochastic analyses of limiting dilution competitive repopulation studies. In this application we will use multiple independent and complimentary biological and mathematical approaches to extend these data to man. We then will simulate myeloproliferative disorders by assuming that a transformed HSC does not require a marrow niche for survival, while a normal HSC needs this microenvironmental support. We will determine if outcomes in virtual individuals are compatible with (a) observations of bcr-abl in normal individuals, CML patients > 10 years after allogeneic transplantation, and CML patients following imatinib therapy (quantitative per data from Jerry Radich, collaborator) and (b) information regarding the time from radiation exposure until the clinical onset of CML, essential thrombocytosis, polycythemia vera, and idiopathic myelofibrosis (data from Hiroshima studies). We anticipate that, once validated, stochastic simulation will be an excellent tool for further studies of the pathogenesis of individual myeloproliferative diseases, disease progression and subclone evolution.
| Catlin, Sandra N; Busque, Lambert; Gale, Rosemary E et al. (2011) The replication rate of human hematopoietic stem cells in vivo. Blood 117:4460-6 |
| Shepherd, Bryan E; Kiem, Hans-Peter; Lansdorp, Peter M et al. (2007) Hematopoietic stem-cell behavior in nonhuman primates. Blood 110:1806-13 |
