CD8⁺ T cell immunosurveillance is crucial in solid tumors and T cell dysfunction leads to tumor progression. In contrast, the role of CD8⁺ T cells in the control of leukemia is less clear. We characterized the molecular signature of leukemia stem/progenitor cells (LSPCs) and paired CD8⁺ T cells in patients with acute myeloid leukemia (AML). Epigenetic alterations via histone deacetylation reduced the expression of immune-related genes in bone marrow (BM)-infiltrating CD8⁺ T cells. Surprisingly, a silenced gene expression pattern in CD8⁺ T cells significantly correlated with an improved prognosis. To define interactions between CD8⁺ T cells and LSPCs, we performed comprehensive correlative network modeling. This analysis indicated that CD8⁺ T cells contribute to the maintenance/expansion of LSPCs, particularly in favorable risk AML. Functionally, CD8⁺ T cells in favorable AML induced the expansion of LSPCs by stimulating the autocrine production of important hematopoietic cytokines such as interleukin (IL)-3. In contrast, LSPCs in aggressive AML were characterized by a higher activation of stemness/proliferation-related pathways and develop independent of BM CD8⁺ T cells. Overall, our study indicates that CD8⁺ T cells support and expand LSPCs in favorable risk AML whereas intermediate and adverse risk AML possess the intrinsic molecular abnormalities to develop independently.