Regulation and Function of Very Long Chain Fatty Acid Biosynthesis in Multiple Myeloma

多发性骨髓瘤(MM)是一种浆细胞疾病，约占所有血液系统恶性肿瘤的10%。 由于内质网(ER)中高水平产生免疫球蛋白G，MM细胞持续承受内质网应激 被认为是这种疾病的“致命弱点”。这一特征使MM容易受到加重的药物的影响 内质网应激，如蛋白酶体抑制剂Bortezomib。然而，目前多发性骨髓瘤对大多数患者来说是无法治愈的，原因是 对蛋白酶体抑制剂迅速产生抗药性。因此，新型抗多发性骨髓瘤药物的鉴定和 目标是非常重要的。 相反，内质网蛋白质输出的增加是对内质网应激的适应性反应的一部分。在 目前的应用，我们提出了一个新的临床相关的途径，控制ER的动态平衡和耐药 通过调节内质网膜鞘磷脂的组成来治疗多发性骨髓瘤。我们的初步数据 提示这种调节影响内质网到高尔基体的转运、内质网稳态，最终影响多发性骨髓瘤细胞的活性。 此外，我们鉴定了3-羟基酰辅酶A脱水酶(HACD3)，这是一种参与生物合成的酶 超长脂肪酸(VLCFA)，作为内质网到高尔基体出口和内质网内稳态的重要调节因子。 重要的是，在多发性骨髓瘤进展过程中和多发性骨髓瘤患者的多发性骨髓瘤细胞中，HACD3mRNA水平升高 对含有硼替佐米的治疗无效。 因此，在具体目标1中，我们将从功能上描述VLCFA依赖的基础机制 内质网稳态的调节及HACD3上下游负责的酶的特性 这样的规定。在特定的目标2中，我们将确定调节MM细胞HACD3mRNA表达的机制。 在具体目标3中，我们将评估VLCFAs在MM小鼠模型中的药理抑制效果。

Multiple Myeloma (MM) is a plasma cell disorder that accounts for ~10% of all hematologic malignancies. Due to high production of IgG in endoplasmic reticulum (ER), MM cells continuously undergo ER stress which is considered an “Achille’s heel” of the disease. This feature makes MM susceptible to the agents that exacerbate ER stress, such as proteasome inhibitor bortezomib. Yet, currently MM is incurable for most patients due to rapidly emerging resistance to proteasome inhibitors. Therefore, identification of novel anti-MM drugs and targets is of high importance. Conversely, an increase in protein export from ER is a part of the adaptive response to ER stress. In the current application, we propose a novel clinically relevant pathway controlling ER homeostasis and resistance to bortezomib in MM via modulation of sphingolipid composition of the ER membrane. Our preliminary data suggest that such modulation affects ER-to-Golgi transport, ER homeostasis and ultimately MM cell viability. Furthermore, we identified 3-hydroxyacyl-CoA dehydratases (HACD3), an enzyme involved in the biosynthesis of very long fatty acids (VLCFA), as an important regulator of ER-to-Golgi export and ER homeostasis. Importantly, HACD3 mRNA levels were increased during MM progression and in MM cells from MM patients refractory to bortezomib-containing therapy. Therefore, in Specific Aim 1, we will functionally characterize mechanisms underlying VLCFA-dependent regulation of ER homeostasis and characterize enzymes upstream and downstream of HACD3 responsible for such regulation. In Specific Aim 2, we will identify mechanisms regulating HACD3 mRNA expression in MM cells. In Specific Aim 3, we will evaluate the efficacy of pharmacological suppression of VLCFAs in MM mouse models.