T-cell acute lymphoblastic lymphoma/leukemia (T-ALL) is a very aggressive malignancy. Targetable molecules/pathways of T-ALL are limited because of an insufficient understanding of its genetics and biology. The applicants’ long-term goal is to advance the knowledge of the molecular processes for the development, proliferation and survival of T-ALL cells, and to translate identified molecular targets into better diagnosis, treatment and prediction of prognosis for T-ALL. Inactivation of PTEN and INK4a/ARF tumor suppressor genes is among the most frequent genetic events in T-ALL. We have generated genetically engineered mouse models of T-ALL deficient for Pten, both Pten and Ink4a/Arf, or Ink4a/Arf. Our preliminary studies revealed the mouse T-ALL resembled the human counterparts genetically, histologically and immunophenotypically. Our Central hypothesis is that aberrant expressions of microRNAs (focusing on miRNA-150 and -155) affects T-ALL cell growth and survival by targeting critical genes that are important for cell growth, differentiation or survival pathways in TALL deficient for Pten, both Pten and Ink4a/Arf, or Ink4a/Arf.