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. 2024 Sep;71(9):e31151.
doi: 10.1002/pbc.31151. Epub 2024 Jul 2.

High DOCK1 expression identifies a distinct prognostic subgroup of pediatric acute myeloid leukemia: Results of the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial

Masahiro Yoshitomi  1 , Shin-Ichi Tsujimoto  1 , Junji Ikeda  1 , Tomoko Kawai  2 , Kentaro Ohki  3 , Yusuke Hara  4 , Genki Yamato  4 , Reo Tanoshima  1   5   6 , Daisuke Tomizawa  7 , Akira Shimada  8 , Keizo Horibe  9 , Souichi Adachi  10 , Takashi Taga  11 , Akio Tawa  12 , Yasuhide Hayashi  13 , Shuichi Ito  1 , Norio Shiba  1
Affiliations

High DOCK1 expression identifies a distinct prognostic subgroup of pediatric acute myeloid leukemia: Results of the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial

Masahiro Yoshitomi et al. Pediatr Blood Cancer. 2024 Sep.

Abstract

Background: The molecular pathogenesis of acute myeloid leukemia (AML) was dramatically clarified over the latest two decades. Several important molecular markers were discovered in patients with AML that have helped to improve the risk stratification. However, developing new treatment strategies for relapsed/refractory acute myeloid leukemia (AML) is crucial due to its poor prognosis.

Procedure: To overcome this difficulty, we performed an assay for transposase-accessible chromatin with sequencing (ATAC-seq) in 10 AML patients with various gene alterations. ATAC-seq is based on direct in vitro sequencing adaptor transposition into native chromatin, and is a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq analysis revealed increased accessibility of the DOCK1 gene in patients with AML harboring poor prognostic factors. Following the ATAC-seq results, quantitative reverse transcription polymerase chain reaction was used to measure DOCK1 gene expression levels in 369 pediatric patients with de novo AML.

Results: High DOCK1 expression was detected in 132 (37%) patients. The overall survival (OS) and event-free survival (EFS) among patients with high DOCK1 expression were significantly worse than those patients with low DOCK1 expression (3-year EFS: 34% vs. 60%, p < .001 and 3-year OS: 60% vs. 80%, p < .001). To investigate the significance of high DOCK1 gene expression, we transduced DOCK1 into MOLM14 cells, and revealed that cytarabine in combination with DOCK1 inhibitor reduced the viability of these leukemic cells.

Conclusions: Our results indicate that a DOCK1 inhibitor might reinforce the effects of cytarabine and other anti-cancer agents in patients with AML with high DOCK1 expression.

Keywords: CBFA2T3::GLIS2; DOCK1; FLT3‐ITD; FUS::ERG; gene expression.

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