Integrative genomic and transcriptomic profiling reveals distinct molecular subsets in adult mixed phenotype acute leukemia.
Qian WangWen-Zhi CaiQin-Rong WangMing-Qing ZhuLing-Zhi YanYan YuXie-Bing BaoHong-Jie ShenHong YaoJun-Dan XieTong-Tong ZhangLing ZhangXiao-Yu XuZhe ShanHong LiuJian-Nong CenDan-Dan LiuJin-Lan PanDa-Ru LuJia ChenYang XuRi ZhangYing WangSheng-Li XueMiao MiaoYue HanXiao-Wen TangHui-Ying QiuAi-Ning SunJin-Yan HuangHai-Ping DaiDe-Pei WuSu-Ning ChenPublished in: American journal of hematology (2022)
Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co-expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T-lymphoid/myeloid MPAL (T/My MPAL-NOS), 42 with Ph+ MPAL, 36 with B-lymphoid/myeloid MPAL (B/My MPAL-NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL-NOS was similar to B/T MPAL-NOS but differed from Ph+ MPAL and B/My MPAL-NOS. T/My MPAL-NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL-NOS showed higher NOTCH1 mutations. By integrating next-generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1-G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement-like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement-like characteristics. Subsequently, we analyzed single-cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease-like and common myeloid progenitor disease-like signatures, G5 and G6 had high expression of granulocyte-monocyte progenitor disease-like and monocyte disease-like signatures, and G7 and G8 had common lymphoid progenitor disease-like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL.
Keyphrases
- single cell
- nitric oxide synthase
- rna seq
- acute myeloid leukemia
- gene expression
- dendritic cells
- bone marrow
- copy number
- healthcare
- newly diagnosed
- ejection fraction
- genome wide
- transcription factor
- nitric oxide
- acute lymphoblastic leukemia
- endothelial cells
- high throughput
- immune response
- big data
- young adults
- single molecule
- artificial intelligence
- binding protein
- deep learning