MOZ is essential for maintenance of hematopoietic stem cells.
Monocytic leukemia zinc-finger protein (MOZ), a MYST family histone acetyltransferase, is involved in the chromosome translocations associated with acute myeloid leukemia. MOZ acts as a transcriptional coactivator for AML1, which is essential for establishment of definitive hematopoiesis. To investigate the roles of MOZ in normal hematopoiesis, we generated MOZ-null mice. MOZ-/- mice died around embryonic day 15 (E15). In MOZ-/- E14.5 embryos, hematopoietic stem cells, lineage-committed progenitors, and B lineage cells were severely reduced. On the other hand, arrest of erythroid maturation and elevated myeloid lineage populations were observed. MOZ-deficient fetal liver cells could not reconstitute hematopoiesis of recipients after transplantation. Analysis using microarray and flow cytometry revealed that expression of thrombopoietin receptor (c-Mpl), HoxA9, and c-Kit was down-regulated. These results show that MOZ is required for maintenance of hematopoietic stem cells, and that it plays a role in differentiation of erythroid and myeloid cells. Some aspects of the MOZ-/- phenotype are similar to that observed in PU.1-deficient mice. MOZ was able to interact with PU.1 and activate PU.1-dependent transcription, thus suggesting a physical and functional link between PU.1 and MOZ.
Katsumoto
Takuo
T
Molecular Oncology Division, National Cancer Institute, Chuo-ku, Tokyo, Japan.
Aikawa
Yukiko
Y
Iwama
Atsushi
A
Ueda
Shinobu
S
Ichikawa
Hitoshi
H
Ochiya
Takahiro
T
Kitabayashi
Issay
I
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics*; D015536:Down-Regulation; D047108:Embryonic Development / Q000235:genetics; D004920:Erythropoiesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics; D007938:Leukemia / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000254:growth & development; D051379:Mice; D008817:Mice, Mutant Strains; D038042:Myelopoiesis / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D018121:Receptors, Cytokine / Q000235:genetics; D053628:Receptors, Thrombopoietin; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D000099232:Proto-Oncogene Protein Spi-1
D051548:Histone Acetyltransferases; D018398:Homeodomain Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C481270:Mpl protein, mouse; C097899:homeobox protein HOXA9; C511438:MOZ protein, mouse