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.
Guo
Yinshi
Y
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153, USA.
Niu
Chao
C
Breslin
Peter
P
Tang
Minghui
M
Zhang
Shubin
S
Wei
Wei
W
Kini
Ameet R
AR
Paner
Gladell P
GP
Alkan
Serhan
S
Morris
Stephan W
SW
Diaz
Manuel
M
Stiff
Patrick J
PJ
Zhang
Jiwang
J
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