ENFORCED TAL-1 EXPRESSION STIMULATES PRIMITIVE, AND MEGAKARYOCYTIC PROGENITORS BUT BLOCKS THE GRANULOPOIETIC DIFFERENTIATION PROGRAM

In human adult hematopoiesis, the TAL-1 gene is up-and downmodulated i n erythropoiesis and granulopoiesis, respectively [G. L. Condorelli et al., Blood, 86: 164-175, 1995]. Here, it is shown that, in a hematopo ietic progenitor cell (HPC) unilineage differentiation culture, tal-1 is induced and then expressed, in a sustained manner, in the megakaryo poietic lineage, whereas it is barely or not detected in the monocytop oietic series. We have investigated the role of enforced tal-1 express ion by retroviral transfer into HPCs [erythroid burst-forming units an d megakaryocytic and granulomonocytic colony-forming units (CFUs)], pr imitive HPCs (high proliferative potential colony-forming cells), and putative hematopoietic stem cells (HSCs), assayed as long-term culture initiating cells. TAL-1 overexpression induces an increase of erythro id burst-forming unit colony number and size and megakaryocytic CFU co lony number and an inhibition of granulomonocytic CFU and granulocytic CFU (CFU-G) but not monocytic CFU colony number; conversely, TAL-1 mu tants with defective heterodimerizing or DNA-binding domains do not ex ert these effects at a significant level. Although it does not affect long-term culture initiating cells, exogenous TAL-1 causes a significa nt proliferative stimulus on primary and secondary high proliferative potential colony-forming cells. In conclusion, exogenous tal-1 exerts differential and stage-and lineage-specific effects on the HPC/HSC dif ferentiation/proliferation gene programs. Thus, it induces a stimulato ry effect at the level of erythroid and megakaryocytic HPCs, while exe rting a selective proliferative action on downstream erythropoiesis. F urthermore, it induces differential effects on the myeloid series: the partial blockade of CFU-G differentiation is possibly linked to the s harp down-modulation of endogenous TAL-1 expression at the level of th e CFU-G-to-granulopoietic precursor differentiation step; in contrast, no significant effect is observed on monocytic CFU colony formation, Finally, the stimulatory effect on primitive HPCs but not putative ste m cells suggests subtle differences in the effects exerted by tal-1 ov erexpression on primitive HPC/HSC subsets in adult life.