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Differential roles of Kras and Pten in murine leukemogenesis

Leukemia volume 27, pages 1210–1214 (2013)Cite this article

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Leukemia is the most common childhood malignancy, accounting for 30% of childhood cancer. Although the causes of leukemia are largely unknown, a few prenatal chromosomal and genetic abnormalities, such as trisomy 21 (Down syndrome) and TEL-AML1 rearrangements, have been linked to an increased risk of childhood leukemia, and studies from twin leukemia have indicated that leukemia can be initiated in utero.1 Both gain-of-functional Kras mutation(s) and loss of Pten (phosphatase and tensin homolog) expression have been implicated in childhood leukemia,2, 3 albeit at a relative low frequency. It remains a plausible hypothesis that these two genetic alternations could occur in utero as an early event, which contributes to postnatal leukemogenesis. Most existing murine models on Kras mutations and Pten deletion use adult bone marrow cells and are not suitable to address this question. In this study, by using fetal-stage blood-lineage-specific non-viral-based genetically modified murine models, we sought to obtain stable and uniformed overexpression or deletion of the gene of interest, to evaluate the effect(s) of deregulated KrasG12D and Pten during fetal hematopoiesis and their potential roles in postnatal leukemogenesis.

Oncogenic Kras mutations, especially on codons 12 and 13, have been identified in pediatric acute lymphoid and myeloid leukemia (ALL and AML) patients.2 Ras are membrane-associated small GTPases and have an important role in transducing signals by cycling between GDP-bound inactivated and GTP-bound activated state.4, 5 Ras gene mutations at codons 12 and 13 lead to hyperactive Ras signaling, which leads to constitutive activation of the Ras protein and affect diverse cellular outcomes, such as cell proliferation/differentiation, survival and malignant transformation.5 Previous studies on conditional oncogenic Kras knock-in adult mice models and bone marrow transduction/transplantation models showed that expression of oncogenic KrasG12D at its endogenous level can induce a lethal myeloproliferative disorder (MPD) as well as transplantable T-lineage acute lymphoblastic leukemia/lymphoma (T-ALL/L) and juvenile myelomonocytic leukemia.6 Here, we used a Vav-iCre model to test the effect of aberrant activation of Kras during fetal murine hematopoietic stage. The Cre recombinase gene in the Vav-iCre transgenic mice is expressed mostly in hematopoietic cells in fetal liver and adult mice.7 By crossing conditional oncogenic KrasG12D mice (LSL-KrasG12D mice; Supplementary Figures 1a and b) with Vav-iCre mice, we can generate a mouse model with blood-lineage-specific expression of activated mutant Kras (KrasG12D) initiated at early fetal hematopoietic stage, and therefore, we can use this non-viral-based system to study the effect(s) of oncogenic Kras in early fetal hematopoiesis.

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Authors and Affiliations

  1. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School Boston, Boston, MA, USA

    P Tang, C Gao, A Li, J Aster & L Chai

  2. Department of Hematology, First Affiliated Hospital to Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

    P Tang & L Sun

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  1. P Tang
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Correspondence to L Sun or L Chai.

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Tang, P., Gao, C., Li, A. et al. Differential roles of Kras and Pten in murine leukemogenesis. Leukemia 27, 1210–1214 (2013). https://doi.org/10.1038/leu.2012.316

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