TG-Interacting Factor 1 expression quantitatively impacts survival in acute myeloid leukemia

Applying transcriptional profiling analysis to myeloblasts from 59 adult patients with acute myeloid leukemia (AML) treated at our institution, we found that expression of the three-amino acid loop extension (TALE) homeobox gene TG-Interacting Factor 1 ( TGIF1 ) correlated with overall and relapse-free survival, which was then confirmed in two other cohorts of patients. Moreover, TGIF1 expression correlated with survival for all cytogenetic risk groups and was an independent prognostic factor in multivariate analysis. To elucidate the mechanism, we used Tgif1 knockout mice in which acute or chronic myeloid leukemia was induced through retroviral transfer of the MLL-AF9 or BCR-ABL fusion genes into bone marrow cells. Loss of Tgif1 accelerated disease progression, shortened survival, attenuated the response to chemotherapy, and doubled the frequency of leukemia-initiating cells. RNA-based sequencing analysis showed that genes associated with transforming growth factor-β (TGF-β) and retinoic acid signaling pathways were differentially affected in Tgif1 -/- compared to Tgif1 +/+ leukemia cells.