Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine (BCM), Houston, TX.
Departments of Pathology and Immunology, Baylor College of Medicine, Houston, TX.
Exp Hematol. 2022 Jun;110:34-38. doi: 10.1016/j.exphem.2022.03.005. Epub 2022 Mar 17.
Children with Down syndrome (DS) are 10-fold more likely to develop B-cell acute lymphoblastic leukemia (B-ALL), with a higher frequency of rearrangements resulting in overexpression of cytokine receptor-like factor 2 (CRLF2). Here, we investigated the impact of CRLF2 overexpression on B-cell progenitor proliferation, immunophenotype, and gene expression profile in the Dp(16)1Yey (Dp16) mouse model of DS compared with wild-type (WT) mice. CRLF2 overexpression enhanced immature B-lymphoid colony development and increased the proportion of less differentiated pre-pro-B cells, with a greater effect in Dp16 versus WT. In CRLF2-rearranged (CRLF2-R) B-ALL patient samples, cells with higher CRLF2 expression exhibited a less differentiated B-cell immunophenotype. CRLF2 overexpression resulted in a gene expression signature associated with E2F signaling both in Dp16 B-progenitors and in DS-ALL patient samples, and PI3K/mTOR and pan-CDK inhibitors, which reduce E2F-mediated signaling, exhibited cytotoxicity in CRLF2-R B-ALL cell lines and patient samples. CRLF2 overexpression alone in Dp16 stem and progenitor cells did not result in leukemic transformation in recipient mice. Thus, CRLF2 overexpression results in reduced B-cell differentiation and enhanced E2F signaling in Dp16 B-progenitor cells and DS-ALL patient samples. These findings suggest a functional basis for the high frequency of CRLF2-R in DS-ALL as well as a potential therapeutically targetable pathway.
唐氏综合征（Down syndrome，DS）患儿发生 B 细胞急性淋巴细胞白血病（B-cell acute lymphoblastic leukemia，B-ALL）的风险增加 10 倍，其细胞因子受体样因子 2（cytokine receptor-like factor 2，CRLF2）重排频率更高，导致其过表达。在此，我们通过 Dp(16)1Yey（Dp16）DS 小鼠模型与野生型（Wild-type，WT）小鼠比较，研究了 CRLF2 过表达对 B 细胞祖细胞增殖、免疫表型和基因表达谱的影响。CRLF2 过表达增强了幼稚 B 淋巴细胞集落的发育，增加了分化程度较低的前 B 细胞的比例，且在 Dp16 中的作用大于 WT。在 CRLF2 重排（CRLF2-rearranged，CRLF2-R）的 B-ALL 患者样本中，表达更高 CRLF2 的细胞表现出更不成熟的 B 细胞免疫表型。CRLF2 过表达导致与 E2F 信号相关的基因表达谱在 Dp16 B 祖细胞和 DS-ALL 患者样本中均发生改变，且抑制 E2F 介导的信号通路的 PI3K/mTOR 和全细胞周期蛋白依赖性激酶（pan-CDK）抑制剂对 CRLF2-R B-ALL 细胞系和患者样本具有细胞毒性。在 Dp16 干细胞和祖细胞中单独过表达 CRLF2 并未导致受者小鼠发生白血病转化。因此，CRLF2 过表达导致 Dp16 B 祖细胞和 DS-ALL 患者样本中的 B 细胞分化减少和 E2F 信号增强。这些发现为 CRLF2-R 在 DS-ALL 中的高频率发生以及潜在的治疗靶向途径提供了功能基础。
