HEMATOPOIESIS 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 differentia-tion in hematopoiesis. Among these is H0XA10, which is selectively expressed at high levels in the most primitive sub-population of human CD341 bone marrow cells. When overexpressed, H0XA10 in-creases the proliferation of early progeni-tor 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 tetracy-cline 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 regulat-able H0XA10 expression in several trans-genic lines. H0XA10 induction led to the formation of hematopoietic colonies con-taining blastlike cells and megakaryo-cytes. Moreover, the induction of H0XA10 resulted in significant proliferative advan-tage of primitive hematopoietic progeni-tors (spleen colony-forming units [CFU-S12]), which was reversible on withdrawal of induction. Activation of H0XA10 expres-sion in tet0-H0XA10 mice will therefore govern proliferation of primitive myeloid progenitors in a regulated fashion. This novel animal model can be used to iden-tify the target genes of HOXA10 and bet-ter clarify the specific role of HOXA10 in normal and malignant hematopoiesis