c-Myc-mediated control of cell fate in megakaryocyte-erythrocyte progenitors.
It has been found that c-Myc protein plays a critical role in controlling self-renewal versus differentiation in hematopoietic stem cells. We report that c-Myc also controls the fate of megakaryocyte-erythrocyte progenitors through regulating the differentiation of erythroid and megakaryocytic progenitors. In addition to the significant reduction of granulocytes/macrophages and B and T lymphocytes because of the reduction of their corresponding progenitors, we found significantly increased numbers of megakaryocytic progenitors and mature megakaryocytes in bone marrow and spleens of c-Myc-knockout (c-Myc(-/-)) mice. Differentiation of erythrocytes was blocked at the erythroid progenitor stage. This increased megakaryocytopoiesis is a cell-intrinsic defect of c-Myc-mutant hematopoietic stem cells, as shown by transplantation studies. Furthermore, we found that c-Myc is required for polyploidy formation but not for cytoplasmic maturation of megakaryocytes. Megakaryocytes from c-Myc(-/-) mice are significantly smaller in size and lower in ploidy than those of control mice; however, because of the dramatic increase in megakaryocyte number, although fewer platelets are produced by each megakaryocyte, a greater than 3-fold increase in platelet number was consistently observed in c-Myc(-/-) mice. Thus, c-Myc(-/-) mice develop a syndrome of severe thrombocytosis-anemia-leukopenia because of significant increases in megakaryocytopoiesis and concomitant blockage of erythrocyte differentiation and reductions in myelolymphopoiesis.
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153, USA.
Yinshi
Y
Guo
Chao
C
Niu
Peter
P
Breslin
Minghui
M
Tang
Shubin
S
Zhang
Wei
W
Wei
Ameet R
AR
Kini
Gladell P
GP
Paner
Serhan
S
Alkan
Stephan W
SW
Morris
Manuel
M
Diaz
Patrick J
PJ
Stiff
Jiwang
J
Zhang
D000740:Anemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D048429:Cell Size; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism*; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D007970:Leukopenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011003:Ploidies; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013922:Thrombocytosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034061:Thrombopoiesis / Q000502:physiology*
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc