HOX-A10 regulates hematopoietic lineage commitment: evidence for a monocyte-specific transcription factor.
Homeobox genes are well known for their crucial role during embryogenesis but have also been found to be critically involved in normal and leukemic hematopoiesis. Because most previous studies focused on the role of aberrant HOX gene expression in leukemogenesis and because HOX-A10 is expressed in human CD34(+) precursor cells, this study investigated whether HOX-A10 also plays a pivotal role in normal hematopoietic-lineage determination. The effect of enforced expression of this transcription factor on hematopoietic differentiation of highly purified human cord-blood progenitors was examined by using in vitro assays. In fetal thymic organ cultures, a dramatic reduction in cells expressing high levels of HOX-A10 was observed, along with absence of thymocytes positive for CD3(+) T-cell receptor alphabeta. Furthermore, in MS-5 stromal cell cultures, there was a 7-fold reduction in the number of natural killer cells and a 9-fold reduction in the number of B cells, thus showing a profound defect in differentiation toward the lymphoid lineage in HOX-A10-transduced progenitors. In contrast, the number of CD14(+) monocytic cells in the stromal cell culture was 6-fold higher, suggesting an enhanced differentiation toward the myeloid differentiation pathway of HOX-A10-transduced progenitors. However, there was a slight reduction in the number of CD15(+) granulocytic cells, which were blocked in their final maturation. These data show that HOX-A10 can act as an important key regulator of lineage determination in human hematopoietic progenitor cells.
Taghon
Tom
T
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent, Belgium.
Stolz
Frank
F
De Smedt
Magda
M
Cnockaert
Maggy
M
Verhasselt
Bruno
B
Plum
Jean
J
Leclercq
Georges
G
D000818:Animals; D001773:Blood Cells / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D005312:Fetal Blood / Q000166:cytology; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D014161:Transduction, Genetic
D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; C092119:Hoxa10 protein, mouse