Identification of IKZF1 genetic mutations as new molecular subtypes in acute myeloid leukaemia

Autor: Yang Wang, Wenyan Cheng, Yvyin Zhang, Yuliang Zhang, Tengfei Sun, Yongmei Zhu, Wei Yin, Jianan Zhang, Jianfeng Li, Yang Shen
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Clinical and Translational Medicine, Vol 13, Iss 6, Pp n/a-n/a (2023)
Druh dokumentu: article
ISSN: 2001-1326
DOI: 10.1002/ctm2.1309
Popis: Abstract Background 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. Methods 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. Results 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. Conclusions 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.
Databáze: Directory of Open Access Journals
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