Quantitative proteomics reveals specific metabolic features of acute myeloid leukemia stem cells

Abstract

Acute Myeloid Leukemia (AML) is characterized by the accumulation of clonal myeloid blast cells unable to differentiate into mature leukocytes. Chemotherapy induces remission in the majority of patients, but relapse rates are high and lead to poor clinical outcomes. Since this is primarily caused by chemotherapy-resistant leukemic stem cells (LSCs), it is essential to eradicate LSCs to improve patient survival. LSCs have predominantly been studied at the transcript level, thus lacking information about post-transcriptionally regulated genes and associated networks. Here we extend our previous report on LSC proteomes to healthy age-matched hematopoietic stem and progenitor cells (HSPCs) and correlate the proteomes to the corresponding transcriptomes. By comparing LSCs to leukemic blasts and healthy HSPCs, we validate candidate LSC markers and highlight novel and potentially targetable proteins that are absent or only lowly expressed in HSPCs. In addition, our data provide strong evidence that LSCs harbor a characteristic energy metabolism, adhesion molecule composition, as well as RNA processing properties. Furthermore, correlating proteome and transcript data of the same individual samples highlights the strength of proteome analyses, which are particularly potent in detecting alterations in metabolic pathways. In summary, our study provides a comprehensive proteomic and transcriptomic characterization of functionally validated LSCs, blasts and healthy HSPCs, representing a valuable resource helping to design LSC-directed therapies.

Scalable, multimodal profiling of chromatin accessibility and protein levels in single cells

“…We anticipate that ASAP-seq, when coupled with large antibody panels which exceed the antigen diversity measurable by current mass cytometry approaches 32 (as demonstrated in this study), may facilitate the discovery of deregulated surface markers on (pre-)malignant/leukemic (stem) cell populations that could be further exploited for diagnostics or antibody-mediated therapies 64, 65 . Further, as showcased by the sensitivity of our measurement of PD-1 in activated T cells ( Fig.…”

Acute Myeloid Leukemia Stem Cells: The Challenges of Phenotypic Heterogeneity

“…Novel technical developments allowing high-throughput screening of low amounts of cells on both transcriptome [ 18 , 25 , 147 ], proteome [ 147 , 148 ], and surface antigen level [ 25 ] may provide further valuable insights into LSC surface antigens (e.g., identification of the fatty acid translocase CD36 and the type 2 C-lectin receptor CD69 via single-cell RNA sequencing [ 67 ]).…”

CKS1-dependent proteostatic regulation has dual roles combating acute myeloid leukemia whilst protecting normal hematopoiesis

“…The selective reduction in viability of CKS1B high AML blasts by CKS1 inhibition (Figure 1D) indicate that, whilst CKS1B is not predictive of overall survival at the RNA level, proteostatic vulnerabilities exist in AML and can be identified through better understanding of leukemic proteomes. While gene expression profiles, particularly those with single cell resolution, are improving our understanding of AML heterogeneity, the origins of leukemic relapse and revealing new clinical targets(25,26), the role of proteostasis has been comparatively understudied(41,42).…”