Department of Medicine, Hematology Section, University of Padova, Via Giustiniani 2, 35128, Padova, Italy.
Venetian Institute of Molecular Medicine, Padova, Italy.
J Hematol Oncol. 2017 Oct 2;10(1):157. doi: 10.1186/s13045-017-0529-5.
Multiple myeloma (MM) is a malignant tumor of transformed plasma cells. MM pathogenesis is a multistep process. This cancer can occur de novo (rarely) or it can develop from monoclonal gammopathy of undetermined significance (most of the cases). MM can be asymptomatic (smoldering myeloma) or clinically active. Malignant plasma cells exploit intrinsic and extrinsic bone marrow microenvironment-derived growth signals. Upregulation of stress-coping pathways is also instrumental to maintain MM cell growth. The phylogenetically related Ser/Thr kinases CSNK1A1 (CK1α) and CSNK2 (CK2) have recently gained a growing importance in hematologic malignancies arising both from precursors and from mature blood cells. In multiple myeloma, CK1α or CK2 sustain oncogenic cascades, such as the PI3K/AKT, JAK/STAT, and NF-κB, as well as propel stress-related signaling that help in coping with different noxae. Data also suggest that these kinases modulate the delivery of growth factors and cytokines from the bone marrow stroma. The "non-oncogene addiction" phenotype generated by the increased activity of CK1α and CK2 in multiple myeloma contributes to malignant plasma cell proliferation and survival and represents an Achilles' heel for the activity of small ATP competitive CK1α or CK2 inhibitors.
多发性骨髓瘤（MM）是一种转化浆细胞的恶性肿瘤。MM 的发病机制是一个多步骤的过程。这种癌症可以是原发性的（很少见），也可以从意义未明的单克隆丙种球蛋白血症（大多数病例）发展而来。MM 可以无症状（冒烟型骨髓瘤）或临床活跃。恶性浆细胞利用内在和外在骨髓微环境衍生的生长信号。应激应对途径的上调对于维持 MM 细胞生长也很重要。在血液恶性肿瘤中，系统发育相关的丝氨酸/苏氨酸激酶 CSNK1A1（CK1α）和 CSNK2（CK2）最近在源自前体细胞和成熟血细胞的恶性肿瘤中越来越受到重视。在多发性骨髓瘤中，CK1α 或 CK2 维持致癌级联反应，如 PI3K/AKT、JAK/STAT 和 NF-κB，以及推进与应激相关的信号转导，帮助应对不同的毒物。数据还表明，这些激酶调节来自骨髓基质的生长因子和细胞因子的传递。在多发性骨髓瘤中，CK1α 和 CK2 活性增加所产生的“非癌基因成瘾”表型有助于恶性浆细胞的增殖和存活，并且是小分子 ATP 竞争 CK1α 或 CK2 抑制剂活性的阿喀琉斯之踵。
