For a study, researchers created a deep-scale proteome and phosphoproteome database using 6 healthy bone marrow-derived controls and 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset.

After ensuring data quality, they orthogonally evaluated several previously unrecognized AML traits revealed by the proteomic data. All AML samples, i.e., generally and patients with recurrent AML driver mutations, found instances of posttranscriptionally regulated proteins. They verified this observation in vitro. For example, samples with IDH1/2 mutations showed higher levels of the 2-oxoglutarate-dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes.

They found many nuclear importins in samples with NPMc mutations, demonstrating that they interact with NPMc but not wild-type NPM1 in samples with these mutations. They found that two cell surface proteins (CD180 and MRC1/CD206) expressed on the AML blasts of many patients (but not on healthy CD34+ stem/progenitor cells) could provide potential targets for immunologic treatments. They further verified these targets using flow cytometry. Finally, they discovered over 30,000 phosphosites in these samples; worldwide, AML samples were connected to aberrant phosphorylation of specific residues in PTPN11, STAT3, AKT1, and PRKCD. Activating tyrosines on the cytoplasmic Src-family tyrosine kinases FGR and HCK and associated signaling proteins were phosphorylated more often in FLT3-TKD samples. TP53-mutant samples revealed prodigious phosphorylation of serine-183 on TP53 itself, while PML-RARA-initiated AML samples presented a distinctive phosphorylation signature.

The freely accessible database would provide a starting point for more research on protein dysregulation’s role in the development of AML.

Reference: ashpublications.org/blood/article/140/13/1533/486036/Proteomic-and-phosphoproteomic-landscapes-of-acute