The PIM serine/threonine kinases have an oncogenic and pro-survival role in hematological and solid cancers. However, the mechanism by which these kinases drive tumor growth has not been completely elucidated. To determine the genes controlled by these protein kinases, we carried out a microarray analysis in T-cell acute lymphoblastic leukemia (T-ALL) comparing early progenitor (ETP-ALL) cell lines whose growth is driven by PIM kinases to more mature T-ALL cells that have low PIM levels. This analysis demonstrated that the long noncoding RNA (lncRNA) H19 was associated with increased PIM levels in ETP-ALL. Overexpression or knockdown of PIM in these T-ALL cell lines controlled the level of H19 and regulated the methylation of the H19 promoter, suggesting a mechanism by which PIM controls H19 transcription. In these T-ALL cells the expression of PIM1 induced stem cell gene expression (SOX2, OCT-4, NANOG) through H19. Identical results were found in prostate cancer cell lines where PIM kinases drive cancer growth, and both H19 and stem cell gene levels. Small molecule pan-PIM inhibitors currently in clinical trials reduced H19 expression in both of these tumor types. Importantly, the knockdown of H19 blocked the ability of PIM to induce stem cell genes in T-ALL cells, suggesting a novel signal transduction cascade. In prostate cancer, increases in SOX2 levels have been shown to cause both resistance to the androgen deprivation therapy (ADT) and the induction of neuroendocrine prostate cancer, a highly metastatic form of this disease. Treatment of prostate cancer cells with a small molecule pan-PIM inhibitor reduced stem cell gene transcription and enhanced ADT, while overexpression of H19 suppressed the ability of pan-PIM inhibitors to regulate hormone blockade. Together these results demonstrate that the PIM kinases control the level of lncRNA H19 which in turn modifies stem cell gene transcription regulating tumor growth.This article is protected by copyright. All rights reserved.