In this study, we report that, while activated Jak/Stat signaling induces transcription target Socs proteins to inhibit Jak/Stat signaling through a negative feedback loop in normal cells, oncogenic N-Ras mutations downregulate Socs2 expression in both mouse pre-leukemic HSPCs and human AML cells, thus leading to hyperactive JAK2-STAT5 signaling and malignant cell expansion. Here, CISH is linked to acute myeloid leukemia.