Mechanistic and functional dissection of myeloid blood cancers

摘要 尽管驱动骨髓性血癌发展的基因已经在很大程度上被确定，但仍有一些基因是不稳定的。 目前，针对这些疾病的有效靶向疗法非常少。这说明需要利用 在过去十年中，通过癌症外显子组测序获得了分子理解， 骨髓恶性肿瘤独特的治疗弱点。我们最近发现了 突变型钙网蛋白（CALR）是骨髓增生性肿瘤（MPN）的致癌基因，MPN是骨髓血的一种亚型 癌的这项工作揭示了以下关键发现：（i）血小板生成素受体，MPL绝对是 所需的突变CALR介导的造血转化，（ii）突变CALR激活JAK/STAT MPL下游的信号传导，和（iii）突变CALR的C-末端是其致癌活性所需的， 通过促进突变CALR和MPL之间的物理相互作用。然而， 突变体CALR和MPL之间的结合激活致病性MPL信号传导仍然是未知的。我将寻求 在本提案的具体目标1中回答这个问题。虽然这种分子机制的剖析 骨髓恶性肿瘤中潜在的致癌蛋白是发展合理的治疗方法的关键一步， 在治疗中，识别细胞中独特的非致癌分子脆弱性可能更为关键 由这些致癌基因转化。近年来，未折叠蛋白反应（UPR）已成为一种新的免疫应答。 癌细胞存活的主要调节因子。UPR协调ER功能的恢复以帮助癌细胞 适应微环境的变化，包括那些破坏氧化还原，钙和代谢稳态。 CALR作为内质网（ER）分子伴侣，是UPR的重要效应子。然而，普遍定期审议在以下方面的作用： 突变CALR驱动的MPN还有待研究。在本提案的具体目标2中，我将确定 突变CALR转化细胞的存活依赖于UPR，以及这种途径是否可以 用于MPN的治疗增益。在本提案的R 00阶段（具体目标3），我将使用 通过对MPN中UPR的研究获得的见解，以调查这一途径是否在更多的疾病中重要。 侵袭性骨髓性血癌，如急性骨髓性白血病（AML）。尽管普遍定期审议已 虽然已证实在髓系白血病发生中发挥作用，但仅在有限数量的 AML的基因亚型。尽管许多AML突变与代谢改变有关， 稳态和可能从事普遍定期审议的结果，这一途径在这种突变的背景下的作用 还有待探索在一个全新的研究路线中，我将专门在遗传子集中询问普遍定期审议， 细胞代谢失调的AML，并确定靶向这一途径是否代表 治疗AML的新途径。

Abstract Although the genes that drive the development of myeloid blood cancers have largely been defined, there are currently very few effective targeted therapies for these diseases. This illuminates the need to exploit the molecular understanding that has been gained in the last decade through cancer exome sequencing to identify unique therapeutic vulnerabilities in myeloid malignancies. We recently identified the mechanism by which mutant calreticulin (CALR) is oncogenic in myeloproliferative neoplasms (MPN), a subtype of myeloid blood cancers. This work revealed the following key findings: (i) The thrombopoietin receptor, MPL is absolutely required for mutant CALR-mediated hematopoietic transformation, (ii) mutant CALR activates JAK/STAT signaling downstream of MPL, and (iii) the C-terminus of mutant CALR is required for its oncogenic activity, through facilitating a physical interaction between mutant CALR and MPL. However, the mechanism by which the binding between mutant CALR and MPL activates pathogenic MPL signaling remains unknown. I will seek to answer this in Specific Aim 1 of this proposal. Although such dissection of the molecular mechanisms underlying oncogenic proteins in myeloid malignancies is a crucial step in developing rational approaches to therapy, it is perhaps even more critical to identify unique, non-oncogenic molecular vulnerabilities in cells transformed by these oncogenes. In recent years, the unfolded protein response (UPR) has emerged as a major regulator of cancer cell survival. The UPR orchestrates the restoration of ER function to help cancer cells adapt to microenvironmental changes, including those that disrupt redox, calcium, and metabolic homeostasis. As an endoplasmic reticulum (ER) chaperone, CALR is a critical UPR effector. However, the role of the UPR in mutant CALR-driven MPN has yet to be studied. In Specific Aim 2 of this proposal, I will determine whether mutant CALR-transformed cells are dependent on the UPR for survival, and whether this pathway can be targeted for therapeutic gain in MPN. In the R00 phase (Specific Aim 3) of this proposal, I will employ the insight gained through the study of the UPR in MPN to investigate whether this pathway is important in more aggressive myeloid blood cancers such as acute myeloid leukemia (AML). Although the UPR has been demonstrated to play a role in myeloid leukemogenesis, it has only been interrogated in a limited number of genetic subtypes of AML. Despite the fact that many AML mutations are associated with altered metabolic homeostasis and likely engage the UPR as a result, the role of this pathway in the context of such mutations has yet to be explored. In an entirely new line of study, I will interrogate the UPR specifically in genetic subsets of AML where cellular metabolism is dysregulated, and determine whether targeting this pathway represents a new therapeutic avenue in the treatment of AML.