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- Björnsson, Jon Mar, et al.
(författare)
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Proliferation of primitive myeloid progenitors can be reversibly induced by HOXA10
- 2001
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Ingår i: Blood. - 1528-0020 .- 0006-4971. ; 98:12, s. 3301-3308
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies show that several Hox transcription factors are important for regulation of proliferation and differentiation in hematopoiesis. Among these is HOXA10, which is selectively expressed at high levels in the most primitive subpopulation of human CD34(+) bone marrow cells. When overexpressed, HOXA10 increases the proliferation of early progenitor cells and can lead to the development of myeloid leukemia. To study the effects of HOXA10 on primitive hematopoietic progenitors in more detail, transgenic mice were generated with regulatable HOXA10 expression. The transgenic mouse model, referred to as tetO-HOXA10, contains the HOXA10 gene controlled by a tetracycline-responsive element and a minimal promoter. Thus, the expression of HOXA10 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 HOXA10 gene In bone marrow cells from the transgenic mice. Reverse transcription-polymerase chain reaction analysis confirmed regulatable HOXA10 expression in several transgenic lines. HOXA10 induction led to the formation of hematopoietic colonies containing blastlike cells and megakaryocytes. Moreover, the induction of HOXA10 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 HOXA10 expression in tet0-HOXA10 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.
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| 2. |
- Björnsson, Jon Mar, et al.
(författare)
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Reduced proliferative capacity of hematopoietic stem cells deficient in hoxb3 and hoxb4
- 2003
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Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 23:11, s. 3872-3883
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Tidskriftsartikel (refereegranskat)abstract
- Several homeobox transcription factors, such as HOXB3 and HOXB4, have been implicated in regulation of hematopoiesis. In support of this, studies show that overexpression of HOXB4 strongly enhances hematopoietic stem cell regeneration. Here we find that mice deficient in both Hoxb3 and Hoxb4 have defects in endogenous hematopoiesis with reduced cellularity in hematopoietic organs and diminished number of hematopoietic progenitors without perturbing lineage commitment. Analysis of embryonic day 14.5 fetal livers revealed a significant reduction in the hematopoietic stem cell pool, suggesting that the reduction in cellularity observed postnatally is due to insufficient expansion during fetal development. Primitive Lin(-) Scal(+) c-kit(+) hematopoietic progenitors lacking Hoxb3 and Hoxb4 displayed impaired proliferative capacity in vitro. Similarly, in vivo repopulating studies of Hoxb3/Hoxb4-deficient hematopoietic cells resulted in lower repopulating capability compared to normal littermates. Since no defects in homing were observed, these results suggest a slower regeneration of mutant HSC. Furthermore, treatment with cytostatic drugs demonstrated slower cell cycle kinetics of hematopoietic stem cells deficient in Hoxb3 and Hoxb4, resulting in increased tolerance to antimitotic drugs. Collectively, these data suggest a direct physiological role of Hoxb4 and Hoxb3 in regulating stem cell regeneration and that these genes are required for maximal proliferative response.
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