Abstract
PTEN acts as a phosphatase for PIP3 and negatively regulates the PI3K/AKT pathway, and p27KIP1 is a cyclin-dependent kinase inhibitor that regulates the G1 to S-phase transition by binding to and regulating the activity of cyclin-dependent kinases. Genetic alterations of PTEN or CDKN1B (p27KIP1) are common in hematological malignancies. To better understand how mutations in these two genes might cooperate in leukemogenesis, we inactivated both genes in the hematological compartment in mice. Here, we show that the combined inactivation of Pten and Cdkn1b results in a more severe myeloproliferative neoplasm phenotype associated with lower hemoglobin, enlarged spleen and liver, and shorter lifespan compared to inactivation of Pten alone. More severe anemia and increased myeloid infiltration and destruction of the spleen contributed to the earlier death of these mice, and elevated p-AKT, cyclin D1, and cyclin D3 might contribute to the development of this phenotype. In conclusion, PTEN and p27KIP1 cooperate in tumor suppression in the hematological compartment.
Highlights
phosphatase and tensin homolog (PTEN) is a tumor suppressor gene located on chromosome 10q23 and is one of the most commonly mutated or deleted genes in human cancers, including acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, and non-Hodgkin’s lymphoma [1, 2]
Consistent with previous studies [13], all Ptenfl/fl Mx1-Cre (PM) mice died from myeloproliferative neoplasm (MPN) by 98 days after pI–pC injections, whereas Cdkn1bfl/fl Mx1-Cre (CM) and Ctrl mice lived much longer and no MPN phenotype was observed in CM mice
Two weeks after pI–pC injections, white blood cell counts were 20.8 × 109 cells/L in Ptenfl/fl Cdkn1bfl/fl Mx1-Cre (PCM) mice compared with mean counts of 18.3 × 109, 13.9 × 109 and 13.6 × 109 cells/L for PM, CM and Ctrl mice, respectively (Fig. 1b)
Summary
PTEN (phosphatase and tension homolog deleted on chromosome 10) is a tumor suppressor gene located on chromosome 10q23 and is one of the most commonly mutated or deleted genes in human cancers, including acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, and non-Hodgkin’s lymphoma [1, 2]. *Correspondence: meng.liu@gu.se 2 Laboratory of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden Full list of author information is available at the end of the article leukemias [5,6,7]. It has been shown that the combined loss of PTEN and p27KIP1 is associated with tumor cell proliferation and increased risk of recurrent disease in localized prostate cancer [10].
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