Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (shanghai), Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Clin Transl Med. 2023 Jun;13(6):e1309. doi: 10.1002/ctm2.1309.
Genetic mutations of IKZF1 have been frequently delineated in B-lineage acute leukaemia (B-ALL) but rarely elucidated in acute myeloid leukaemia (AML). IKZF1 mutations confer a poor prognosis in AML, and hotspot mutations of IKZF1, N159Y and N159S tend to occur in B-ALL and AML respectively. However, the pathogenesis of IKZF1 N159S in AML and IKZF1 lineage susceptibility are largely unknown.
The genetic and clinical characteristics of IKZF1-mutated AML patients were evaluated. Multi-omics analysis and functional assays were performed in vitro using IKZF1 mutations knock-in AML cell lines.
23 (4.84%) small sequence variants of IKZF1 were identified in 475 newly diagnosed AML (non-M3) patients. Based on RNA sequencing, three classes of IKZF1-related AML were defined, including 9 patients (39.13%) with IKZF1 N159S mutations, 10 (43.47%) with CEBPA mutations and 4 others (17.39%). IKZF1 N159S may define a unique subgroup with higher HOXA/B expression and native B-cell immune fractions. Gene expression data of multiple knock-in cell lines indicate that the lymphocyte differentiation-related MME and CD44 kept high expression in IKZF1 N159Y but were downregulated in N159S. CUT&TAG sequencing showed that IKZF1 N159S reshaped the binding profiles of IKZF1. Integration analysis suggested that the pathogenesis of IKZF1 N159S may depend on the deregulation of several cofactors, such as oncogenic MYC and CPNE7 targets.
Collectively, we dissected the molecular spectrum and clinical features of IKZF1-related AML, which may promote an in-depth understanding of the pathogenesis, lineage susceptibility and clinical research of AML.
IKZF1 的基因突变在 B 细胞急性白血病（B-ALL）中经常被描绘，但在急性髓系白血病（AML）中很少被阐明。IKZF1 突变在 AML 中预示预后不良，而 IKZF1 的热点突变 N159Y 和 N159S 分别倾向于发生在 B-ALL 和 AML 中。然而，IKZF1 N159S 在 AML 中的发病机制和 IKZF1 谱系易感性在很大程度上尚不清楚。
评估了 IKZF1 突变型 AML 患者的遗传和临床特征。使用 IKZF1 突变敲入 AML 细胞系进行体外的多组学分析和功能测定。
在 475 例新诊断的 AML（非 M3）患者中鉴定出 23 个（4.84%） IKZF1 小序列变异。基于 RNA 测序，定义了三种 IKZF1 相关的 AML 类型，包括 9 例（39.13%）患者具有 IKZF1 N159S 突变，10 例（43.47%）患者具有 CEBPA 突变，还有 4 例（17.39%）其他患者。IKZF1 N159S 可能定义了一个具有更高 HOXA/B 表达和天然 B 细胞免疫分数的独特亚群。多个敲入细胞系的基因表达数据表明，淋巴细胞分化相关的 MME 和 CD44 在 IKZF1 N159Y 中保持高表达，但在 N159S 中下调。CUT&TAG 测序显示 IKZF1 N159S 重塑了 IKZF1 的结合谱。整合分析表明，IKZF1 N159S 的发病机制可能依赖于几个共因子的失调，如致癌 MYC 和 CPNE7 靶点。
总的来说，我们剖析了 IKZF1 相关 AML 的分子谱和临床特征，这可能有助于深入了解 AML 的发病机制、谱系易感性和临床研究。
