Proliferation of primitive myeloid progenitors can be reversibly induced by HOXA10.
Recent studies show that several Hox transcription factors are important for regulation of proliferation and differentiation in hematopoiesis. Among these is H0XA10, which is selectively expressed at high levels in the most primitive subpopulation of human CD34(+) bone marrow cells. When overexpressed, H0XA10 increases the proliferation of early progenitor cells and can lead to the development of myeloid leukemia. To study the effects of H0XA10 on primitive hematopoietic progenitors in more detail, transgenic mice were generated with regulatable H0XA10 expression. The transgenic mouse model, referred to as tetO-HOXA10, contains the H0XA10 gene controlled by a tetracycline-responsive element and a minimal promoter. Thus, the expression of H0XA10 is inducible and reversible depending on the absence or presence of tetracycline or its analog, doxycycline. A retroviral vector containing the tetracycline transactivator gene (tTA) was used to induce expression of the H0XA10 gene in bone marrow cells from the transgenic mice. Reverse transcription-polymerase chain reaction analysis confirmed regulatable H0XA10 expression in several transgenic lines. H0XA10 induction led to the formation of hematopoietic colonies containing blastlike cells and megakaryocytes. Moreover, the induction of H0XA10 resulted in significant proliferative advantage of primitive hematopoietic progenitors (spleen colony-forming units [CFU-S(12)]), which was reversible on withdrawal of induction. Activation of H0XA10 expression in tet0-H0XA10 mice will therefore govern proliferation of primitive myeloid progenitors in a regulated fashion. This novel animal model can be used to identify the target genes of HOXA10 and better clarify the specific role of HOXA10 in normal and malignant hematopoiesis.
Björnsson
J M
JM
Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University Hospital, Lund, Sweden.
Andersson
E
E
Lundström
P
P
Larsson
N
N
Xu
X
X
Repetowska
E
E
Humphries
R K
RK
Karlsson
S
S
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D007951:Leukemia, Myeloid / Q000209:etiology; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D023421:Models, Animal; D020218:Response Elements / Q000187:drug effects; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013752:Tetracycline / Q000494:pharmacology
D018952:Antigens, CD34; D004268:DNA-Binding Proteins; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C092119:Hoxa10 protein, mouse; D013752:Tetracycline; D004318:Doxycycline