Integrative proteogenomic and pharmacological landscape of acute myeloid leukaemia

Acute myeloid leukaemia (AML) is mainly characterized by an increase in the number of myeloid cells in the bone marrow and a decrease in mature cells, accounting for 28% of leukaemia cases, with a five-year survival rate of only 30.5%.

More recently, quantitative proteomics analyses uncovered the heterogeneity of Western AML patients at the protein and phosphorylation modification levels, However, there is still a lack of drug sensitivity integrated with a more comprehensive multi-omics characterization, which could promote a deeper understanding of AML molecular characteristics and their relationship to drug responses. Moreover, the proteomics of Asian populations is still poorly understood.  

To address this, Professor Jia Li, Professor Yubo Zhou, Professor Minjia Tan research team from Shanghai Institute of Materia Medica and Professor Jianmin Yang research team from Naval Medical University presented a comprehensive genomic, proteomic and phosphoproteomic analysis of 101 Chinese AML samples and systemic in vitro drug sensitivity analysis of 77 drugs. proteome-based unsupervised clustering revealed three subtypes with different molecular characterizations and clinical outcomes. Further integrative analysis of drug sensitivity combined with proteomic/phosphoproteomic data uncovered potential drug combinations (Fig.1).  

The study employed consensus clustering to identify AML subtypes. The results showed that three subtypes were more considerable than two or four subtypes (Fig.2). No obvious prognostic difference was observed among the three subtypes (log rank test, P > 0.05). However, the study found that the Measurable residual disease (MRD) after treatment was higher in S-I, which reflected the lower clearing efficiency.

In addition, the study showed that allogenic haematopoietic stem cell transplantation (Allo-SCT) did not prolong the survival of patients in S-I (log rank test, P > 0.05). However, patients with types S-II&III significantly benefited from Allo-SCT. These results indicated that Allo-SCT might be a potential treatment strategy for subtype S-II&III.

To further understand the correlation between drug sensitivity and molecular characteristics, Based on two rounds of high-throughput screening (2247 compounds screened initially and 285 compounds screened again), the study profiled primary tumour cells from 56 patient samples against a panel of 77 inhibitors involving clinical chemotherapy drugs, kinase inhibitors and epigenetic inhibitors (Fig.3).

The study showed that higher expression of ALDH3A2 was positively correlated with the cytarabine sensitivity value. The study used a combination of the ALDH3A2 inhibitor disulfiram and cytarabine to treat 10 AML cell lines. Substantial synergistic effects (Highest Single Agency (HSA) model) were observed, indicating that disulfiram could sensitize the therapeutic efficacy of cytarabine in most of the cell lines. In addition, the multi-omics data provided a good opportunity to investigate the underlying molecular characteristics of Acalisib (PI3K inhibitor) resistance. In the Spearman correlation analysis of the drug sensitivity and the abundance of a single phosphosite, the study found that the highest kinase activation of PDK calculated by KSEA was observed to be related to low Acalisib sensitivity. Further drug combination via simultaneously targeting PDK using its inhibitor GSK2334470 could improve the anticancer effect of Acalisib and another PI3K inhibitor, GDC0032.

In conclusion, the multi-omic integrative analysis of the study revealed valuable insight for linking molecular characterizations with clinical outcomes and provided an additional molecular layer beyond AML genetic and proteomic characterization for potential diagnosis and therapeutic strategies.

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