Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity.,Cancer Cell

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Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity.
Cancer Cell ( IF 48.8 ) Pub Date : 2018-01-08 , DOI: 10.1016/j.ccell.2017.11.012
Hiroyoshi Kunimoto ₁ , Cem Meydan ₂ , Abbas Nazir ₁ , Justin Whitfield ₁ , Kaitlyn Shank ₁ , Franck Rapaport ₃ , Rebecca Maher ₄ , Elodie Pronier ₁ , Sara C Meyer ₅ , Francine E Garrett-Bakelman ₆ , Martin Tallman ₇ , Ari Melnick ₈ , Ross L Levine ₉ , Alan H Shih ₉

Affiliation

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
University of Connecticut School of Medicine, Farmington, CT 06032, USA.
Division of Hematology, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY 10065, USA; Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY 10065, USA; Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and Nras^G12D expression in hematopoietic cells induced myeloid transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML), which was serially transplantable. Tet2 loss and Nras mutation cooperatively led to decrease in negative regulators of mitogen-activated protein kinase (MAPK) activation, including Spry2, thereby causing synergistic activation of MAPK signaling by epigenetic silencing. Tet2/Nras double-mutant leukemia showed preferential sensitivity to MAPK kinase (MEK) inhibition in both mouse model and patient samples. These data provide insights into how epigenetic and signaling mutations cooperate in myeloid transformation and provide a rationale for mechanism-based therapy in CMML patients with these high-risk genetic lesions.

中文翻译：

TET2 缺失和 NRAS 突变的协同表观遗传重塑驱动髓样转化和 MEK 抑制剂敏感性。

表观遗传修饰因子和信号因子的突变通常在髓系恶性肿瘤中同时发生，包括 TET2 和 NRAS 突变。并发 Tet2 丢失和 Nras ^G12D造血细胞中的表达诱导骨髓转化，具有完全渗透性、致死性慢性粒单核细胞白血病 (CMML)，可连续移植。Tet2 丢失和 Nras 突变共同导致丝裂原活化蛋白激酶 (MAPK) 激活的负调节因子减少，包括 Spry2，从而通过表观遗传沉默导致 MAPK 信号的协同激活。Tet2/Nras 双突变白血病在小鼠模型和患者样本中均表现出对 MAPK 激酶 (MEK) 抑制的优先敏感性。这些数据提供了对表观遗传和信号突变如何在骨髓转化中协同作用的见解，并为具有这些高风险遗传病变的 CMML 患者的基于机制的治疗提供了理论依据。

更新日期：2017-12-21

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