DEREGULATED EXPRESSION OF C-MYC IN MEGAKARYOCYTES OF TRANSGENIC MICE INCREASES MEGAKARYOPOIESIS AND DECREASES POLYPLOIDIZATION

Platelets, essential for vascular integrity and hemostasis, fragment f rom polyploid megakaryocytes, characterized by their endomitotic cell cycle. We studied the influence of overexpression of c-myc oncogene on megakaryopoiesis and endomitosis in vivo, using transgenic mice carry ing c-myc fused to the estrogen receptor under the control of the plat elet factor 4 (PF4) megakaryocyte-specific promoter. The rationale beh ind this strategy was to obtain controlled overexpression of an active c-Myc, depending on the estrogen level in the mouse circulation. Anal ysis of these transgenic mice revealed that the bone marrow of female transgenic mice or of estrogen-injected male transgenic mice, but not of age-matched transgenic males nor nontransgenic females, contained f requent immature myeloid cells and an increased number of megakaryocyt es. Deregulated expression of c-Myc shifted the normal ploidy profile of megakaryocytes due to a significant increase in proliferating megak aryocytes and a decrease in the fraction of ploidizing cells. These tr ansgenic mice represent a novel in vivo model for a Myc induced myelop roliferative disorder which can be controlled.