Proteomic and phosphoproteomic landscapes of acute myeloid leukemia

Abstract

We have developed a deep-scale proteome and phosphoproteome database from 44 representative Acute Myeloid Leukemia (AML) patients from the LAML TCGA dataset, and 6 healthy bone marrow derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of post-transcriptionally regulated proteins both globally (i.e. in all AML samples), and also, in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2‑oxoglutarate-dependent histone demethylases KDM4A/B/C, despite no changes in mRNA levels for these genes; we confirmed this finding in vitro. In samples with NPMc mutations, we identified several nuclear importins with post‑transcriptionally increased protein abundance, and showed that they interact with NPMc, but not wildtype NPM1. We identified two cell surface proteins (CD180 and MRC1/CD206) expressed on AML blasts of many patients (but not healthy CD34+ stem/progenitor cells) that could represent novel targets for immunologic therapies, and confirmed these targets via flow cytometry. Finally, we detected nearly 30,000 phosphosites in these samples; globally, AML samples were associated with the abnormal phosphorylation of specific residues in PTPN11, STAT3, AKT1 and PRKCD. FLT3‑TKD samples were associated with increased phosphorylation of activating tyrosines on the cytoplasmic Src-family tyrosine kinases FGR and HCK, and related signaling proteins. PML-RARA-initiated AML samples displayed a unique phosphorylation signature, and TP53-mutant samples showed abundant phosphorylation of serine-183 on TP53 itself. This publicly available database will serve as a foundation for further investigations of protein dysregulation in AML pathogenesis.

M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism

“…S1E). From these 92, five genes ( MRC1 , CD163 , FGR , GASK1B , and RASA3 ) could predict overall survival (OS) in at least two AML cohorts and were differentially expressed between the paired CD34 + or CD34 − compartments of patients with AML [except for MRC1 , mainly due to monocytic blasts ( 20 )] (fig. S1F).…”

Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children

“…A few studies have performed global proteomics and phosphoproteomics on AML patient material (e.g., [9][10][11][12][13][14][15][16][17]). The studies carried out thus far mainly served to identify diagnostic or prognostic markers, or to investigate the efficacy of novel treatments.…”

FBXO22 promotes leukemogenesis by targeting BACH1 in MLL-rearranged acute myeloid leukemia

“…Moreover, the decrease of BACH1 protein under cycloheximide (CHX) treatment was dramatically blocked in FBXO22 knockout THP-1 cells (F i g. 5 I). Furthermore, we analyzed the correlation between FBXO22 and BACH1 protein expression in the proteomic database of AML (PXD032110) [ 39 ]. The results showed that the protein expression of FBXO22 was negatively correlated with BACH1 protein level in primary AML patients, and patients with higher FBXO22 protein expression had lower BACH1 protein expression and vice versa (Fig.…”