Precursor B cell acute lymphoblastic leukemia (BCP-ALL) constitutes the leading cause of cancer-related death in children. While chromosomal alterations contribute to BCP-ALL pathogenesis, they are insufficient for leukemia development. Epidemiological data and evidence from a mouse model suggest that immune responses to infections may trigger the emergence of leukemia, but the mechanisms remain unclear. Here, we show that T helper (Th) cells from bone marrow of pediatric BCP-ALL patients can be attracted and activated by autologous BCP-ALL cells. Bone-marrow Th cells supportively interacted with BCP-ALL cells, inducing upregulation of important surface molecules and BCP-ALL cell proliferation. These Th cells displayed a Th1-like phenotype and produced high levels of IFN-γ. IFN-γ was responsible for the upregulation of CD38 in BCP-ALL cells, a molecule which we found to be associated with early relapse, and accountable for the production of IP-10, a chemokine involved in BCP-ALL migration and drug resistance. Thus, our data provide mechanistic support for an involvement of Th cell immune responses in the propagation of BCP-ALL and suggest that BCP-ALL cell-supportive Th cells may serve as therapeutic target.