Targeting the Core Binding Factor tumor suppressor in MLL-fusion AML

描述(申请人提供)：RUNX1被认为是髓系肿瘤中一种有益的肿瘤抑制药。RUNX1功能抑制是核心结合因子(CBF)白血病和MLL融合白血病发生发展的重要机制之一。失活RUNX1突变常见于急性髓系白血病(AML)患者。然而，RUNX1突变通常是杂合性的，在AML中RUNX1的完全缺失是罕见的，在具有共同融合蛋白的AML中未发现体细胞RUNX1突变，如CBF和MLL融合白血病。这些数据表明，急性髓系白血病的生存和生长需要一定(低)水平的RUNX1活性。我们通过将白血病融合蛋白导入人脐血CD34+细胞，建立了急性髓系白血病的人体模型。表达MLL-AF9的脐带血细胞移植到免疫缺陷小鼠体内会导致人类白血病。我们最近发现，这些AML细胞严重依赖RUNX1活性来持续生长和存活，这表明RUNX1是一种有前途的AML治疗策略。我们将阐明RUNX1介导的AML细胞存活/生长的分子机制，并将这些发现转化为临床，在人AML的小鼠异种移植模型中使用一种新的RUNX1抑制剂。这项研究将为所提出的策略提供原则性证据，并将作为有用的临床前初步数据用于临床应用。

DESCRIPTION (provided by applicant): RUNX1 is considered a beneficial tumor suppressor in myeloid neoplasms. Inhibition of RUNX1 function has been implicated as an important mechanistic event in the development of core-binding factor-(CBF)-leukemia and MLL-fusion leukemia. Inactivating RUNX1 mutations are frequently found in patients with acute myeloid leukemia (AML). However, RUNX1 mutation is usually heterozygous, complete loss of RUNX1 in AML is rare and no somatic RUNX1 mutation have been found in AMLs with common fusion proteins, such as CBF- and MLL-fusion leukemias. These data raise the possibility that a certain (low) level of RUNX1 activity is required for survival and growth of AML. We have developed human models for AML by transducing leukemogenic fusion proteins into human cord blood CD34+ cells. MLL-AF9-expressing cord blood cells cause human leukemia when transplanted into immunodeficient mice. We recently found that these AML cells critically depend on RUNX1 activity for sustained growth and survival, indicating that RUNX1 is a promising therapeutic strategy for AML. We will clarify molecular mechanisms underlying RUNX1-mediated survival/growth of AML cells and translate these findings into the clinic, using a novel RUNX1 inhibitor in murine xenograft models of human AML. This study will provide a proof of principle to the proposed strategy, and will serve as useful preclinical preliminary data for clinical application.