Acute monoblastic and monocytic leukemia is a distinct subtype of acute myeloid leukemia (AML)(also known as AML-FAB subtype M5) and comprises B5 to 10% of all cases of AML. AML-M5 is currently treated with chemotherapy (such as anthracyclines) and/or with bone marrow transplantation. The development of more specific and effective therapies was hampered in part by the lack of proper animal models for this subtype of leukemia. Here, we report a mouse model for this entity. This is the first and the only relevant nonviral-based animal model for human monocytic leukemia. One commonly used strategy for generating mouse solid tumor or leukemia models is to enhance the strength of tumorpromoting signals. One such signal is PtdIns (3, 4, 5) P3/Akt signaling pathway. PtdIns (3, 4, 5) P3 exerts its function by mediating protein translocation by binding to their pleckstrin homolog domains. PKB/Akt, a pleckstrin homolog domain containing serine/threonine protein kinase with oncogenic and anti-apoptotic activities, is one of the major downstream factors of PtdIns (3, 4, 5) P3. Hyperactivation of PtdIns (3, 4, 5) P3/Akt signaling pathway is frequently identified in a variety of cancers and is highly related to tumorigenesis. It has also been implicated in leukemia tumorigenesis. About 50–70% of AMLs display hyperactivation of this pathway. 1 Accordingly, we examined whether monocytic leukemia can be induced by specifically enhancing PtdIns (3, 4, 5) P3 signaling in myeloid cells. PtdIns (3, 4, 5) P3 signaling was elevated by disrupting the tumor suppressor phosphatase and tensin homolog (PTEN), a phosphatidylinositol 30-phosphatase that converts PtdIns (3, 4, 5) P3 to PtdIns (4, 5) P2. Depletion of this lipid phosphatase led to accumulation of PtdIns (3, 4, 5) P3 on the plasma membrane and thus elevation of PtdIns (3, 4, 5) P3/Akt signaling. PTEN disruption in hematopoietic stem cells led to the development of both AML and acute lymphoblastic leukemia. 2, 3 To achieve myeloid-specific PTEN deletion, we used a conditional PTEN knockout (KO) mouse, in which two loxP sequences were inserted on either side of the exon 5 of PTEN encoding the phosphatase domain. We crossed this mouse with a myeloid-specific Cre line (The Jackson Lab, Bar Harbor, ME, USA), in which the Cre recombinase gene was inserted into the endogenous M lysozyme locus, and therefore is under the control of myeloid-specific lysozyme promoter. As a result, only in myeloid linage, the loxP site was cut by Cre recombinase, leading to the disruption of PTEN. 4–6 Mice that are homozygous for this allele were viable, fertile, normal in size, had normal blood count and did not display any gross physical or behavioral abnormalities up to 3 months of age. 4–6 Neutrophils isolated from these mice were more sensitive to chemoattractant stimulation and displayed prolonged survival. PTEN disruption also significantly enhanced neutrophil recruitment at sites of infection. In a bacterial pneumonia model, elevating PtdIns (3, 4, 5) P3 by disrupting PTEN enhanced recruitment of neutrophils to the inflamed lungs, delayed the apoptotic death and enhanced the bacteria killing capability of the recruited neutrophils. 4–6 Leukemogenesis was observed in 11 of 18 PTEN KO mice examined. It occurred in mice older than 3 months. Peripheral blood smear showed numerous blasts (> 20% of nucleated cells), which were intermediate to large in size, and had irregular to bilobed nuclei, dispersed chromatin, distinct nucleoli and moderate amount of cytoplasm (Figure 1a). Bone marrow aspirate smear also showed numerous blasts with similar morphological features (> 20% of nucleated cells …