The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois.
Committee on Cancer Biology, University of Chicago, Chicago, Illinois.
Blood Cancer Discov. 2022 Jul 6;3(4):298-315. doi: 10.1158/2643-3230.BCD-21-0144.
Approximately 20% of patients with myeloproliferative neoplasms (MPN) harbor mutations in the gene calreticulin (CALR), with 80% of those mutations classified as either type I or type II. While type II CALR-mutant proteins retain many of the Ca2+ binding sites present in the wild-type protein, type I CALR-mutant proteins lose these residues. The functional consequences of this differential loss of Ca2+ binding sites remain unexplored. Here, we show that the loss of Ca2+ binding residues in the type I mutant CALR protein directly impairs its Ca2+ binding ability, which in turn leads to depleted endoplasmic reticulum (ER) Ca2+ and subsequent activation of the IRE1α/XBP1 pathway of the unfolded protein response. Genetic or pharmacologic inhibition of IRE1α/XBP1 signaling induces cell death in type I mutant but not type II mutant or wild-type CALR-expressing cells, and abrogates type I mutant CALR-driven MPN disease progression in vivo.
Current targeted therapies for CALR-mutated MPNs are not curative and fail to differentiate between type I- versus type II-driven disease. To improve treatment strategies, it is critical to identify CALR mutation type-specific vulnerabilities. Here we show that IRE1α/XBP1 represents a unique, targetable dependency specific to type I CALR-mutated MPNs. This article is highlighted in the In This Issue feature, p. 265.
约 20%的骨髓增殖性肿瘤 (MPN) 患者存在钙网织蛋白 (CALR) 基因突变，其中 80%的突变可分为 I 型或 II 型。虽然 II 型 CALR 突变蛋白保留了野生型蛋白中存在的许多 Ca2+结合位点，但 I 型 CALR 突变蛋白会失去这些残基。这种 Ca2+结合位点差异缺失的功能后果仍未得到探索。在这里，我们表明 I 型突变 CALR 蛋白中 Ca2+结合残基的丢失直接损害了其 Ca2+结合能力，进而导致内质网 (ER) Ca2+耗竭，随后激活未折叠蛋白反应的 IRE1α/XBP1 途径。IRE1α/XBP1 信号通路的遗传或药理学抑制会诱导 I 型突变而非 II 型突变或野生型 CALR 表达细胞死亡，并在体内消除 I 型突变 CALR 驱动的 MPN 疾病进展。
目前针对 CALR 突变 MPN 的靶向治疗并非根治性的，且无法区分 I 型与 II 型驱动的疾病。为了改善治疗策略，识别 CALR 突变类型特异性脆弱性至关重要。在这里，我们表明 IRE1α/XBP1 代表了 I 型 CALR 突变性 MPN 特有的、可靶向的依赖性。本文在本期的特色文章中进行了重点介绍，第 265 页。
