CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The extensively validated 30% of positive CLL cells cut-off value is able to separate CLL patients into two subgroups with different prognosis, but it does not consider the pattern of CD49d expression. In the present study, we analysed a cohort of 1,630 CLL samples and identified the presence of ~20% of CLL cases (n=313) characterized by a bimodal expression of CD49d, i.e. concomitant presence of a CD49dpos sub-population and a CD49dneg sub-population. At variance with the highly stable CD49d expression observed in CLL patients with a homogeneous pattern of CD49d expression, CD49d bimodal CLL showed a higher level of variability in sequential samples, and an increase in the CD49dpos sub-population over time after therapy. The CD49dpos sub-population from CD49d bimodal CLL displayed higher levels of proliferation compared to the CD49dneg cells, was more highly represented in the bone marrow compared to peripheral blood (PB), and in PB CLL subsets expressing the CXCR4dim/CD5bright phenotype, known to be enriched in proliferative cells. From a clinical standpoint, CLL patients with CD49d bimodal expression, regardless of whether the CD49dpos sub-population exceeded or not the 30% cut-off, experienced a clinical behavior similar to CD49dpos CLL, both in the chemo-immunotherapy (n=1,522) and in the ibrutinib (n=158) settings. Altogether, these results suggest that CD49d can drive disease progression in CLL, and that the pattern of CD49d expression should be also considered to improve the prognostic impact of this biomarker in CLL.

中文翻译：

---

CD49d 促进慢性淋巴细胞白血病的疾病进展：CD49d 双峰表达的新见解

CD49d 是一种显着的慢性淋巴细胞白血病 (CLL) 预后生物标志物。广泛验证的 30% 阳性 CLL 细胞临界值能够将 CLL 患者分为具有不同预后的两个亚组，但它没有考虑 CD49d 表达的模式。在本研究中，我们分析了 1,630 个 CLL 样本的队列，并确定了约 20% 的 CLL 病例（n = 313）的存在，其特征在于 CD49d 的双峰表达，即同时存在 CD49dpos 亚群和 CD49dneg 亚群-人口。与在具有均质 CD49d 表达模式的 CLL 患者中观察到的高度稳定的 CD49d 表达不同，CD49d 双峰 CLL 在连续样本中显示出更高水平的变异性，并且 CD49dpos 亚群在治疗后随时间增加。与 CD49dneg 细胞相比，来自 CD49d 双峰 CLL 的 CD49dpos 亚群显示出更高的增殖水平，与外周血 (PB) 相比，在骨髓中的表现更高，并且在表达 CXCR4dim/CD5bright 表型的 PB CLL 亚群中，已知富含增殖细胞。从临床角度来看，具有 CD49d 双峰表达的 CLL 患者，无论 CD49dpos 亚群是否超过 30% 截止值，都经历了与 CD49dpos CLL 相似的临床行为，无论是在化学免疫治疗中（n = 1,522）在依鲁替尼 (n=158) 设置中。总之，这些结果表明 CD49d 可以驱动 CLL 中的疾病进展，并且还应考虑 CD49d 表达模式以改善该生物标志物在 CLL 中的预后影响。