Modulation of the myeloid differentiation block in acute myeloid leukemia II

目前对急性髓细胞白血病（AML）的治疗是骨髓毒性的，并且使患者在数周内对感染并发症没有保护，通常具有致命的后果。为了快速恢复AML患者的免疫功能，我们需要直接诱导白血病原始细胞分化为功能性免疫细胞。这种治疗的主要障碍是我们对AML中的分化阻滞的理解不足，例如对维甲酸（ATRA）信号的抗性。在过去的三年中，我们已经取得了相当大的进展，了解阻断髓样分化的组成部分，通过研究致癌基因MN 1的机制。MN 1在人细胞中诱导ATRA抗性并转化人造血祖细胞。MN 1抑制与癌基因MEIS 1一致的免疫应答信号的基因，但不抑制ATRA的受体RARA。此外，我们发现证据表明RARA被MN 1置换，因此假设RARA置换诱导AML对维甲酸信号传导的抗性。我们建议1）验证原代人AML细胞中的RARA置换，2）功能性表征置换RARA的蛋白质，3）开发脂质/siRNA制剂作为诱导分化的治疗靶点。我们的项目解决了白血病发生的一个关键方面，到目前为止，人们对这个方面的了解还很少，并且可能对其他领域产生更广泛的影响，例如诱导多能干细胞分化为功能免疫细胞。

Current treatments for acute myeloid leukemia (AML) are myelotoxic and leave patients unprotected against infectious complications for several weeks with often fatal consequences. To quickly restore immune function in AML patients, we need to directly induce differentiation of leukemic blasts to functioning immune cells. The major obstacle of such treatments has been our insufficient understanding of the differentiation block in AML, exemplified by the resistance to retinoic acid (ATRA) signaling. During the last three years we have made considerable progress in understanding the components of blocked myeloid differentiation by studying the mechanism of the oncogene MN1. MN1 induces ATRA resistance in human cells and transforms human hematopoietic progenitor cells. MN1 represses genes of the immune response signature in concert with the oncogene MEIS1, but not with RARA, the receptor for ATRA. Moreover, we found evidence that RARA is displaced by MN1 and therefore hypothesize that RARA displacement induces resistance to retinoic acid signaling in AML. We propose to 1) verify RARA displacement in primary human AML cells, 2) functionally characterize the proteins that displace RARA and 3) develop lipid/siRNA formulations as differentiation-inducing therapeutic targets. Our project addresses a critical aspect of leukemogenesis that is poorly understood so far and may have wider implications for other areas like differentiation of induced pluripotent stem cells to functioning immune cells.