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 doublings (NbD) undergone by individual megakaryocyte progenitors before commitment to polyploidization are markedly skewed and can consistently be fitted to straight lines when plotted on semilogarithmic coordinates. The slope of such lines, which yields the probability of polyploidization per doubling, 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 study of clonal heterogeneity in a hemopoietic lineage, which is the subject of this review.


METHODS
Articles relevant to the interpretation of these data were selected from the authors' and public databases.


RESULTS
Exponential NbD distributions were first explained by postulating that following the assembly of thrombopoiesis-specific regulators, megakaryocyte progenitors require only a single random event to arrest proliferation and commit to polyploidization. However, this stochastic model was refuted by data indicating that intrinsic properties of individual progenitors affect the NbD they achieve. We suggest that the unequal repartition of critical compounds (including receptors, signaling molecules, and gene regulators) inherent in the stem cell-progenitor transition causes a heritable heterogeneity in megakaryocyte progenitor responsiveness to polyploidization inducers. This model would be compatible with 1) the evidence for intraclonal synchronization in megakaryocyte and other hemopoietic clones generated by committed progenitors; 2) the low probability of polyploidization of 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.


CONCLUSIONS
The responsiveness of individual megakaryocyte progenitors to polyploidization inducers may be a major determinant of the exponential shape of NbD distributions.
Paulus
J M
JM
Laboratory of Hematology and Service of Medical Statistics, Hôpital du Sart Tilman, University of Liège, 4000 Liège, Belgium. jeanmichel.paulus@chu.ulg.ac.be
Levin
J
J
Debili
N
N
Albert
A
A
Vainchenker
W
W
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D016922:Cellular Senescence; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects; D014644:Genetic Variation; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D011123:Polyploidy; D051381:Rats; D013269:Stochastic Processes
D008934:Mitogens