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

Wang, Yang; Cheng, Wen‐Yan; Zhang, Yvyin; Zhang, Yuliang; Sun, Tengfei; Zhu, Yong‐Mei; Yin, Wei; Zhang, Jianan; Li, Jianfeng; Shen, Yang

doi:10.1002/ctm2.1309

Cited by 5 publications

(5 citation statements)

References 49 publications

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“…In our large cohort of 1606 adult AML patients, we found heterozygous SNVs to be the most common mode of alteration while we observed only four frame-shift mutations and only one small deletion of IKZF1 . In accordance with previous results [ 37 , 39 ], we also identified a mutational hotspot in the second N-terminal zinc finger domain at p.N159S, which was present in 19 cases (42.2%). Furthermore, in our cohort alterations were restricted to exons 5–8 while no alterations were detected in exons 1–3.…”

Section: Discussionsupporting

confidence: 92%

“…While the authors describe a significantly reduced CR rate for patients with IKZF1 mutations, they did not find a difference in RFS or OS in their overall cohort, however, for patients with high mutational burden of IKZF1 (VAF > 0.2), OS was significantly reduced [ 38 ]. Wang et al [ 39 ] found 23 (4.8%) of 475 AML patients to bear mutated IKZF1 . In RNA sequencing, they delineated three clusters of IKFZ -mutated patients: N159S (40%), co-occurring CEBPA mutations (43%), and others (17%) [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Wang et al [ 39 ] found 23 (4.8%) of 475 AML patients to bear mutated IKZF1 . In RNA sequencing, they delineated three clusters of IKFZ -mutated patients: N159S (40%), co-occurring CEBPA mutations (43%), and others (17%) [ 39 ]. They report higher expression of HOXA/B as well as native B-cell fractions with IKZF1 N159S suggesting a deregulation of MYC and CPNE7 targets in pathogenesis [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…While its frequency and impact on patient outcome are well established in ALL, the clinical significance of IKZF1 alterations is less clear in AML. Previous studies have reported the frequency of altered IKZF1 in AML to range between 1.2% in a pediatric cohort of 258 patients [ 36 ] and 2.6% to 4.8% in three adult cohorts including 193, 475, and 522 patients, respectively [ 37 – 39 ]. Given the overlapping functions of IKZF1 in the regulation of both lymphatic and myeloid differentiation, an investigation into the clinical implications of altered IKZF1 in AML in a large scale study seems warranted.…”

Section: Introductionmentioning

confidence: 99%

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Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia

Eckardt,

Stasik,

Röllig

et al. 2023

Leukemia

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Genetic lesions of IKZF1 are frequent events and well-established markers of adverse risk in acute lymphoblastic leukemia. However, their function in the pathophysiology and impact on patient outcome in acute myeloid leukemia (AML) remains elusive. In a multicenter cohort of 1606 newly diagnosed and intensively treated adult AML patients, we found IKZF1 alterations in 45 cases with a mutational hotspot at N159S. AML with mutated IKZF1 was associated with alterations in RUNX1, GATA2, KRAS, KIT, SF3B1, and ETV6, while alterations of NPM1, TET2, FLT3-ITD, and normal karyotypes were less frequent. The clinical phenotype of IKZF1-mutated AML was dominated by anemia and thrombocytopenia. In both univariable and multivariable analyses adjusting for age, de novo and secondary AML, and ELN2022 risk categories, we found mutated IKZF1 to be an independent marker of adverse risk regarding complete remission rate, event-free, relapse-free, and overall survival. The deleterious effects of mutated IKZF1 also prevailed in patients who underwent allogeneic hematopoietic stem cell transplantation (n = 519) in both univariable and multivariable models. These dismal outcomes are only partially explained by the hotspot mutation N159S. Our findings suggest a role for IKZF1 mutation status in AML risk modeling.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia

Eckardt,

Stasik,

Röllig

et al. 2023

Leukemia

View full text Add to dashboard Cite

show abstract

“…Wang Y et al. found that 23 out of 475 (4.8%) AML patients bear mutated IKZF1 , and delineated three clusters of IKZF -mutated as: N159S (40%), co-occurring CEBPA mutations (43%), and others (17%) ( 102 ). Jäger et al.…”

Section: Roles Of Ikzf1 Mutations In Leukemiamentioning

confidence: 99%

Multifaceted roles of IKZF1 gene, perspectives from bench to bedside

Feng,

Zhang,

Liu

2024

Front. Oncol.

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The IKZF1 gene encodes a transcription factor that belongs to the family of zinc-finger DNA-binding proteins associated with chromatin remodeling. The protein product, IKAROS, had been proved to regulate lymphopoiesis. Subsequent mouse model studies have further confirmed its regulating role in lymphopoiesis as well as in hematopoiesis; besides, it associates with immune function, certain immune disorders like common variable immunodeficiency and dysgammaglobulinemia have been proved to be associated with germline IKZF1 mutations. Dysfunction of IKAROS also bears paramount significance in leukemic transformation and alterations of IKZF1 gene predicts a poor prognosis in hematological malignancies. As an independent prognostic marker, IKZF1 has been incorporated in the risk stratification of BCP-ALL and stratification-guided therapy has also been generated. In this review, we provide a concise and comprehensive overview on the multifaceted roles of IKZF1 gene.

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