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Integrated analysis reveals distinct molecular, clinical, and immunological features of B7-H3 in acute myeloid leukemia.

ABSTRACT: The role of B7-H3 in acute myeloid leukemia (AML) is not fully understood. Two previous studies investigating its expression and significances in AML are partially different. In this study, we aimed to systematically characterize the genomic and immune landscape in AML patients with altered B7-H3 expression using multi-omics data in the public domain. We found significantly increased B7-H3 expression in AML compared to either other hematological malignancies or healthy controls. Clinically, high B7-H3 expression was associated with old age, TP53 mutations, wild-type WT1 and CEBPA, and the M3 and M5 FAB subtypes. Moreover, we observed that increased B7-H3 expression correlated significantly with a poor outcome of AML patients in four independent datasets. Gene set enrichment analysis (GSEA) revealed the enrichment of the "EMT" oncogenic gene signatures in high B7-H3 expressers. Further investigation suggested that B7-H3 was more likely to be associated with immune-suppressive cells (macrophages, neutrophils, dendritic cells, and Th17 cells). B7-H3 was also positively associated with a number of checkpoint genes, such as VISTA (B7-H5), CD80 (B7-1), CD86 (B7-2), and CD70. In summary, we uncovered distinct genomic and immunologic features associated with B7-H3 expression in AML. This may lead to a better understanding of the molecular mechanisms underlying B7-H3 dysregulation in AML and to the development of novel therapeutic strategies.

SUBMITTER: Zhang LY

PROVIDER: S-EPMC8559480 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background Acute myeloid leukemia (AML) is a heterogeneous and aggressive blood cancer that results from diverse genetic aberrations in the hematopoietic stem or progenitor cells (HSPCs) leading to the expansion of blasts in the hematopoietic system. The heterogeneity and evolution of cancer blasts can render therapeutic interventions ineffective in a yet poorly understood patient-specific manner. In this study, we investigated the clonal heterogeneity of diagnosis (Dx) and relapse (Re) pairs at genetic and transcriptional levels, and unveiled the underlying pathways and genes contributing to recurrence. Methods Whole-exome sequencing was used to detect somatic mutations and large copy number variations (CNVs). Single cell RNA-seq was performed to investigate the clonal heterogeneity between Dx-Re pairs and amongst patients. Results scRNA-seq analysis revealed extensive expression differences between patients and Dx-Re pairs, even for those with the same -presumed- initiating events. Transcriptional differences between and within patients are associated with clonal composition and evolution, with the most striking differences in patients that gained large-scale copy number variations at relapse. These differences appear to have significant molecular implications, exemplified by a DNMT3A/FLT3-ITD patient where the leukemia switched from an AP-1 regulated clone at Dx to a mTOR signaling driven clone at Re. The two distinct AML1-ETO pairs share genes related to hematopoietic stem cell maintenance and cell migration suggesting that the Re leukemic stem cell-like (LSC-like) cells evolved from the Dx cells. Conclusions In summary, the single cell RNA data underpinned the tumor heterogeneity not only amongst patient blasts with similar initiating mutations but also between each Dx-Re pair. Our results suggest alternatively and currently unappreciated and unexplored mechanisms leading to therapeutic resistance and AML recurrence. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-022-01635-4.

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Integrated analysis reveals distinct molecular, clinical, and immunological features of B7-H3 in acute myeloid leukemia.

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