Abstract
Abstract Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm (MPN) caused by the constitutively activated BCR-ABL tyrosine kinase. CML progresses from an initial chronic phase, through an accelerated phase, to a final and fatal blast crisis. Current first-line therapy for CML involves tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, or nilotinibs. However, TKIs don't completely cure CML, as revealed by low complete molecular response rate and frequent disease relapse upon drug withdrawal. Studies of patient samples and mouse models indicate that this most likely results from lack of dependence of CML stem cells (CML-SCs) on BCR-ABL for survival. It is important to further identify potential targets of CML-SC. Shp2 is a non-receptor protein tyrosine phosphatase involed in RTK, cytokine, and integrine signaling pathways, and is a target of Abl kinase during cell proliferation. It is required for survival and maintenance of normal hematopoietic stem cells (HSCs). In the context of CML, BCR-ABL constitutively phosphorylates Gab2, which then binds to Shp2, resulting in its inappropriate activation of downstream pathways, including the Ras-Erk cascade. Gab2 is required for CML initiation in vivo. We hypothesized that Shp2 is required for CML development from the stem cell level and might be an effective target for treatment of CML. Using our induced Shp2 deletion tools, we found that Shp2 is required for CML initiation and maintenance in a bone marrow transplant model of CML. Moreover, primitive CML cells undergo elevated cell death upon Shp2 knockout. This implicates Shp2 as a potential target for CML therapy in future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1352. doi:1538-7445.AM2012-1352
Published Version
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