Division of Hematology, University Hospitals, Geneva, Switzerland.
Department of Pathology, Medicine Faculty, Geneva, Switzerland.
Leukemia. 2015 Sep;29(9):1901-8. doi: 10.1038/leu.2015.68. Epub 2015 Mar 10.
Multiple myeloma (MM) is a non-curable tumor developing in the bone marrow (BM). The BM microenvironment rich in hematopoietic precursors is suspected to have a role in MM development. Here we show that a proliferation-inducing ligand (APRIL) mediated in vivo MM promotion. In MM-infiltrated BM, APRIL originated from differentiating myeloid cells with an expression peak in precursor cells. Notably, APRIL expression stayed stable in BM despite MM infiltration. The pool of APRIL-producing cells changed upon MM infiltration. Although CD16(+) mature myeloid cells constituted about half of the APRIL-producing cells in healthy BM, CD16(-) Elastase(+) myeloid precursor cells were predominant in MM-infiltrated BM. Myeloid precursor cells secreted all the APRIL they produced, and binding of secreted APRIL to MM cells, strictly dependent of heparan sulfate carried by CD138, resulted in an in situ internalization by tumor cells. This indicated APRIL consumption by MM in BM. Taken together, our data show that myelopoiesis dysregulation characterized by an increased proportion of precursor cells occurs in MM patients. Such dysregulation correlates with a stable expression of the MM-promoting factor APRIL in infiltrated BM.
多发性骨髓瘤（MM）是一种在骨髓（BM）中发展的不可治愈的肿瘤。富含造血前体的 BM 微环境被怀疑在 MM 发展中起作用。在这里，我们展示了一种增殖诱导配体（APRIL）介导的体内 MM 促进作用。在 MM 浸润的 BM 中，APRIL 来源于分化的髓样细胞，在前体细胞中表达峰值最高。值得注意的是，尽管 MM 浸润，APRIL 表达仍在 BM 中保持稳定。APRIL 产生细胞的池在 MM 浸润时发生变化。尽管 CD16(+)成熟髓样细胞构成健康 BM 中 APRIL 产生细胞的一半左右，但在 MM 浸润的 BM 中，CD16(-)弹性蛋白酶(+)髓样前体细胞占优势。髓样前体细胞分泌它们产生的所有 APRIL，并且分泌的 APRIL 与 MM 细胞的结合，严格依赖于由 CD138 携带的肝素硫酸盐，导致肿瘤细胞的原位内化。这表明 APRIL 在 BM 中被 MM 消耗。总之，我们的数据表明，在 MM 患者中发生了以前体细胞比例增加为特征的髓样细胞分化失调。这种失调与浸润 BM 中促进 MM 的因子 APRIL 的稳定表达相关。
