Genesis of clone size heterogeneity in megakaryocytic and other hemopoietic colonies: The stochastic model revisited

Objective. We previously showed that the distributions of the numbers of do ublings (NbD) undergone by individual megakaryocyte progenitors before comm itment to polyploidization are markedly skewed and can consistently be fitt ed to straight lines when plotted on semilogarithmic coordinates. The slope of such lines, which yields the probability of polyploidization per doubli ng, is made less steep by stimulators of megakaryocyte colony formation and is less steep in mixed erythroid-megakaryocyte than in pure megakaryocyte colonies. Therefore, megakaryocytopoiesis provides a unique model for the s tudy of clonal heterogeneity in a hemopoietic lineage, which is the subject of this review. Data Sources. Articles relevant to the interpretation of these data were se lected from the authors' and public databases. Data Synthesis. Exponential NbD distributions were first explained by postu lating that following the assembly of thrombopoiesis-specific regulators, m egakaryocyte progenitors require only a single random event to arrest proli feration and commit to polyploidization. However, this stochastic model was refuted by data indicating that intrinsic properties of individual progeni tors affect the NbD they achieve. We suggest that the unequal repartition o f critical compounds (including receptors, signaling molecules, and gene re gulators) inherent in the stem cell-progenitor transition causes a heritabl e heterogeneity in megakaryocyte progenitor responsiveness to polyploidizat ion inducers. This model would be compatible with 1) the evidence for intra clonal synchronization in megakaryocyte and other hemopoietic clones genera ted by committed progenitors; 2) the low probability of poly ploidization o f the relatively insensitive bipotent megakaryocyte progenitors; and 3) the thesis that stimulators act in part by recruiting megakaryocyte progenitor cells endowed with lesser responsiveness to polyploidization inducers and higher proliferative potential. Conclusion. The responsiveness of individual megakaryocyte progenitors to p olyploidization inducers may be a major determinant of the exponential shap e of NbD distributions. (C) 2001 International Society for Experimental Hem atology. Published by Elsevier Science Inc.