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The regulation of gene transcription is elementary for the function of hematopoietic stem cells (HSCs). The transcriptional repressor growth factor independence 1 (Gfi1) restricts HSC proliferation and is essential to maintain their self‐renewal capacity and multipotency after transplantation. In addition,  Gfi1  −/−  HSCs are severely compromised in their ability to compete with wild‐type ( wt ) HSCs after transplantation. We now report that Gfi1 protects HSCs against stress‐induced apoptosis, probably, by repressing the proapoptotic target gene  Bax , since irradiated  Gfi1  −/−  HSCs display higher expression of Bax and show a higher rate of apoptosis than  wt  HSCs. This protective function of Gfi1 appears to be functionally relevant since  Gfi1  −/−  HSCs that express Bcl‐2, which antagonizes the effects of Bax, regain their ability to self renew and to initiate multilineage differentiation after transplantation. Surprisingly,  Gfi1  −/− x Bcl‐2  transgenic mice also show a strong, systemic expansion of Mac‐1 + Gr‐1 −  myeloid cells in bone marrow and peripheral lymphoid organs. These cells express high levels of the proleukemogenic transcription factor Hoxa9 and, in older mice, appear as atypical monocytoid‐blastoid cells in the peripheral blood. As a result of this massive expansion of myeloid cells, all  Gfi1  −/− x Bcl‐2  mice eventually succumb to a myeloproliferative‐like disease resembling a preleukemic state. In summary, our data demonstrate that Gfi1's ability to protect against apoptosis is essential for HSC function. In addition, our finding show that Gfi1 prevents the development of myeloproliferative diseases and provides evidence how Gfi1 deficiency could be linked to myeloid leukemia. S TEM  C ELLS  2011;29:376–385

stem cells

Growth Factor Independence 1 Protects Hematopoietic Stem Cells Against Apoptosis but Also Prevents the Development of a Myeloproliferative‐Like Disease