Baert L, Manfroi B, Quintero M, Chavarria O, Barbon P V, Clement E, Zeller A, Van Kuppevelt T, Sturm N, Moreaux J, Tveita A, Bogen B, McKee T, Huard B
Institute for Advanced Biosciences, University Grenoble-Alpes, INSERM U1209, La Tronche, France.
translational innovation in medicine and complexity, University Grenoble-Alpes, CNRS UMR5525, La Tronche, France.
Matrix Biol. 2023 Jun;120:60-75. doi: 10.1016/j.matbio.2023.05.005. Epub 2023 May 16.
Multiple myeloma is a hematological neoplasm derived from plasma cells invariably developing in the bone marrow (BM). The persisting clinical challenge in MM resides in its high ability to resist drugs as shown by the frequent relapses observed in patients regardless of the treatment applied. In a mouse model of MM, we identified a subpopulation of cells harboring increased resistance to current MM drugs. These cells bound a proliferation inducing ligand (APRIL), a key MM promoting/survival factor. APRIL binding involved the heparan sulfate (HS) chain present on syndecan-1 (SDC-1), and correlated with reactivity to the anti-HS antibody 10e4. 10e4cells had a high proliferation activity, and were able to form colonies in 3-D cultures. 10e4 cells were the only cells able to develop in BM after intravenous injection. They also resisted drugs in vivo, since their number increased after treatment in BM. Notably, 10e4 cells differentiated into 10e4 cells upon in vitro and in vivo expansion. Expression of one sulfotransferase, HS3ST3a1, allowed modification of syndecan-1 to confer reactivity to 10e4 and binding to APRIL. HS3ST3a1 deletion inhibited tumorigenesis in BM. Notably, the two populations coexisted at a variable frequency in the BM of MM patients at diagnosis. In total, our results indicate that 3-O-sulfation on SDC-1 carried out by HS3ST3a1 defines aggressive MM cells, and that targeting of this enzyme could possibly be used to better control drug resistance.
多发性骨髓瘤是一种起源于骨髓中浆细胞的血液系统肿瘤。多发性骨髓瘤持续存在的临床挑战在于其具有很强的耐药性，无论采用何种治疗方法，患者都经常复发。在多发性骨髓瘤的小鼠模型中，我们鉴定出了一个对当前多发性骨髓瘤药物耐药性增强的细胞亚群。这些细胞结合增殖诱导配体（APRIL），这是一种促进多发性骨髓瘤发生/存活的关键因子。APRIL的结合涉及硫酸乙酰肝素（HS）链，该链存在于多配体蛋白聚糖-1（SDC-1）上，并与抗HS抗体10e4的反应性相关。10e4细胞具有高增殖活性，并且能够在三维培养中形成集落。10e4细胞是静脉注射后唯一能够在骨髓中生长的细胞。它们在体内也具有耐药性，因为在骨髓中接受治疗后其数量增加。值得注意的是，10e4细胞在体外和体内扩增后仍分化为10e4细胞。一种硫酸转移酶HS3ST3a1的表达能够修饰多配体蛋白聚糖-1，使其具有对10e4的反应性并与APRIL结合。HS3ST3a1的缺失抑制了骨髓中的肿瘤发生。值得注意的是，在诊断时，这两个细胞亚群以不同频率共存于多发性骨髓瘤患者的骨髓中。总的来说，我们的结果表明，由HS3ST3a1介导的SDC-1上的3-O-硫酸化定义了侵袭性多发性骨髓瘤细胞，靶向这种酶可能有助于更好地控制耐药性。
