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 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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MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Hematologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Hematology (hsv//eng)

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