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. 2024 May 10;6(2):e00188.
doi: 10.1097/BS9.0000000000000188. eCollection 2024 Apr.

The RTK-RAS signaling pathway is enriched in patients with rare acute myeloid leukemia harboring t(16;21)(p11;q22)/ FUS::ERG

Anli Lai  1   2 , Wenbing Liu  1   2 , Hui Wei  1   2   3 , Ying Wang  1   2   3 , Dong Lin  1   2 , Chunlin Zhou  1   2 , Bingcheng Liu  1   2 , Runxia Gu  1   2 , Yan Li  1   2 , Shuning Wei  1   2 , Benfa Gong  1   2 , Kaiqi Liu  1   2 , Xiaoyuan Gong  1   2 , Yuntao Liu  1   2 , Guangji Zhang  1   2 , Junping Zhang  1   2 , Yingchang Mi  1   2   3 , Jianxiang Wang  1   2   3 , Shaowei Qiu  1   2   3
Affiliations

The RTK-RAS signaling pathway is enriched in patients with rare acute myeloid leukemia harboring t(16;21)(p11;q22)/ FUS::ERG

Anli Lai et al. Blood Sci. .

Abstract

Acute myeloid leukemia (AML) with t(16;21)(p11;q22)/FUS::ERG is a rare AML subtype associated with poor prognosis. However, its clinical and molecular features remain poorly defined. We determined the clinicopathological, genomic, and transcriptomic characteristics and outcomes of patients with AML harboring FUS::ERG at our center. Thirty-six AML patients harboring FUS::ERG were identified, with an incidence rate of 0.3%. These patients were characterized by high lactate dehydrogenase levels (median: 838.5 U/L), elevated bone marrow blast counts (median: 71.5%), and a CD56-positive immunophenotype (94.3%). Notably, we found that RTK-RAS GTPase (RAS) pathway genes, including NRAS (33%) and PTPN11 (24%), were frequently mutated in this subtype. Transcriptome analysis revealed enrichment of the phosphatidylinositol-3-kinase-Akt (PI3K-Akt), mitogen-activated protein kinase (MAPK), and RAS signaling pathways and upregulation of BCL2, the target of venetoclax, in FUS::ERG AML compared to RUNX1::RUNX1T1 AML, a more common AML subtype with good prognosis. The median event-free survival in patients with FUS::ERG AML was 11.9 (95% confidence interval [CI]: 9.0-not available [NA]) months and the median overall survival was 18.2 (95% CI: 12.4-NA) months. Allogeneic hematopoietic stem cell transplantation failed to improve outcomes. Overall, the high incidence of RTK-RAS pathway mutations and high expression of BCL2 may indicate promising therapeutic targets in this high-risk AML subset.

Keywords: Acute myeloid leukemia; BCL2; RTK-RAS signaling pathway; q22)/FUS::ERG; t(16; 21)(p11.

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Conflict of interest statement

Conflict of interest: The authors declare that they have no conflict of interest.

Figures

Figure 1.
Figure 1.
Genomic landscape of patients with t(16;21)(p11;q22)/FUS::ERG AML. (A) Oncoplot displaying recurrent cytogenetic abnormalities and hotspot mutations. (B) Functional categories of the mutated genes. AML = acute myeloid leukemia, NA = not available, RNA-seq = RNA sequencing, Targeted-seq = targeted sequencing, WES = whole exome sequencing.
Figure 2.
Figure 2.
Transcriptome characteristics of patients with FUS::ERG AML compared with the normal control group. (A) PCA results of all expressing genes. (B) Unsupervised hierarchical clustering of top 2000 variable genes. (C) KEGG enrichment analysis depicting biologic terms associated with upregulated genes in patients with FUS::ERG AML. (D) Volcano plot indicating the upregulated and downregulated genes. (E) Gene set enrichment analysis plot showing the gene set associated with leukemia stem cells. AML = acute myeloid leukemia, KEGG = Kyoto Encyclopedia of Genes and Genomes, MAPK = mitogen-activated protein kinase, NC = normal control, NES = normalized enrichment score, padj-value = adjusted P value, PCA = principal component analysis, PI3K-Akt = phosphatidylinositol-3-kinase-Akt, RAS = RAS GTPase.
Figure 3.
Figure 3.
Transcriptome characteristics of patients with FUS::ERG compared with RUNX1::RUNX1T1 AML (A) PCA results of all expressing genes. (B) Unsupervised hierarchical clustering of top 2000 variable genes. (C) KEGG enrichment analysis depicting biologic terms associated with upregulated genes in patients with FUS::ERG versus RUNX1::RUNX1T1 AML. (D) Heatmap depicting the relative expression value of the top 20 genes most associated with cNMF C1 and C2 subgroups. (E) Boxplot showing the expression value of BCL2 in the 2 fusion-gene groups, *P < .05, ●: outlier. AML = acute myeloid leukemia, cNMF = consensus non-negative matrix factorization, KEGG = Kyoto Encyclopedia of Genes and Genomes, MAPK = mitogen-activated protein kinase, PCA = principal component analysis, PI3K-Akt = phosphatidylinositol-3-kinase-Akt, RAS = RAS GTPase, VST = variant stabilizing transformation using DESeq2.
Figure 4.
Figure 4.
Clinical outcome of patients with FUS::ERG AML. (A–B) Kaplan–Meier curves showing the EFS and OS of patients with FUS::ERG AML and the reference groups; (C–D) Simon–Makuch plot depicting the effect of HSCT in patients with FUS::ERG AML who finally achieved CR. AML = acute myeloid leukemia, CR = complete remission, EFS = event-free survival, HSCT = hematopoietic stem cell transplantation, OS = overall survival.
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