ABOUT

  SUMMARY

      Acute myeloid leukemia (AML) exhibits a considerable degree of heterogeneity and is shaped by a complex interplay of genetic and epigenetic events, predominantly affecting the elderly population. While a few breakthroughs have beeen achieved in the treatment of AML since 2017, the long-term survival remains dismal for elderly patients under current treatment paradigms. Despite numerous studies (including our own) elucidating the genomic and transcriptomic profiles of AML, efforts focusing on post-transcriptional regulatory landscapes/mechanisms of the disease remain scarce. To date, a stable disease classification scheme based on proteomics has not yet been established, especially within the context of the latest World Health Organization (WHO) classification system. Furthermore, the proteomic signatures indicative of hematopoietic aging in AML remain to be comprehensively delineated. Hence, it is imperative to thoroughly characterize proteomic subtypes and intricate mechanisms that connect aging with the development of AML, particularly within a large-scale cohort study.

      We report a comprehensive multi-omics cohort of 374 newly diagnosed AML patients encompassing a wide spectrum of cytogenetic and genetic subtypes. Through integrated analysis of proteomic, phosphoproteomic, genomic, transcriptomic, and drug screening data (also visually illustrated above with the overview of our study conceptualization), we present the following key findings:
    • Characterization of genotype-phenotype correlations in AML. Despite the modest correlation between all protein-mRNA pairs, differentially expressed proteins in key genetic subtypes exhibit a higher association with their corresponding mRNA levels. This strongly suggests that driver mutations or fusion genes may exert a greater impact on protein abundance and disease phenotypes.
    • Establishment of proteomic subtypes in AML. Employing the similarity network fusion (SNF) clustering algorithm, we successfully delineate eight proteomic subtypes with distinct clinical and molecular properties. This proteome-guided subtyping demonstrates robust consistency and even augments the existing WHO classification schema for AML.
    • Identifying the abundance of proteins and phosphosites associated with aging. Pathways associated with immune and inflammatory responses and hematopoietic lineage commitment, particularly megakaryocyte- and platelet-related signatures, emerge as the most significant alterations observed during the aging process. Age-related phosphosites reflect distinct kinase activation in elderly AML patients.
    • Construction of the hematopoietic aging score. A hematopoietic aging score has been established, which captures patients with high-risk and aging-related molecular aberrations and demonstrates an independent adverse prognostic value in AML. A higher score is associated with mutations in myelodysplasia-related, NPM1, and clonal hematopoiesis-related genes.

  WORKFLOW

      Workflow of the proteomic and phosphoproteomic analysis: This study included bone marrow samples from 374 AML patients collected at the time of first diagnosis. Sample preparation steps for proteome and phosphoproteome analysis included cell isolation, cell lysis, protein extraction and digestion, and additional enrichment of phosphopeptides before data independent acquisition (DIA) and data-dependent acquisition (DDA) on the mass spectrometer. After batch effect correction, the off-machine data were entered into a series of downstream bioinformatics analysis.

  KEY PAPERS

    Aging and comprehensive molecular profiling in acute myeloid leukemia

    PNAS 2024

    DOI: 10.1073/pnas.2319366121

    Identification of IKZF1 genetic mutations as new molecular subtypes in acute myeloid leukaemia

    Clinical Translational Medicine 2023

    DOI: 10.1002/ctm2.1309

    Characteristic immunophenotype and gene co-mutational status orchestrate to optimize the prognosis of CEBPA mutant acute myeloid leukemia

    Blood Cancer Journal 2023

    DOI: 10.1038/s41408-023-00838-2

    Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia

    PNAS 2022

    DOI: 10.1073/pnas.2211429119

    Optimization of idarubicin and cytarabine induction regimen with homoharringtonine for newly diagnosed acute myeloid leukemia patients based on the peripheral blast clearance rate: A single-arm, phase 2 trial (RJ-AML 2014)

    American Journal of Hematology 2022

    DOI: 10.1002/ajh.26386

    Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial)

    PNAS 2021

    DOI: 10.1073/pnas.2020382118

    Integration of Genomic and Transcriptomic Markers Improves the Prognosis Prediction of Acute Promyelocytic Leukemia

    Clinical Cancer Research 2021

    DOI: 10.1158/1078-0432.CCR-20-4375

    Multidimensional study of the heterogeneity of leukemia cells in t(8;21) acute myelogenous leukemia identifies the subtype with poor outcome

    PNAS 2020

    DOI: 10.1073/pnas.2003900117

    Development and validation of a prognostic model for adult patients with acute myeloid leukaemia

    EBioMedicine 2020

    DOI: 10.1016/j.ebiom.2020.103126

    Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet

    Blood 2019

    DOI: 10.1182/blood-2019-01-894980

    Gene mutational pattern and expression level in 560 acute myeloid leukemia patients and their clinical relevance

    Journal of Translational Medicine 2017

    DOI: 10.1186/s12967-017-1279-4

    Mutations of Epigenetic Modifier Genes as a Poor Prognostic Factor in Acute Promyelocytic Leukemia Under Treatment With All-Trans Retinoic Acid and Arsenic Trioxide

    EBioMedicine 2015

    DOI: 10.1016/j.ebiom.2015.04.006

    Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia

    Blood 2011

    DOI: 10.1182/blood-2011-03-343988

    Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia

    Nature Genetics 2011

    DOI: 10.1038/ng.788

    PML/RARalpha targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia

    Cancer Cell 2010

    DOI: 10.1016/j.ccr.2009.12.045

    Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML

    Science 2010

    DOI: 10.1126/science.1183424

    All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia

    PNAS 2004

    DOI: 10.1073/pnas.0400053101

  LEAD CONTACT


    CHEN Sai-Juan M.D. & Ph.D ()

      Member, Chinese Academy of Engineering

      Professor & Director

      State Key Laboratory of Medical Genomics

      Shanghai Institute of Hematology

      National Research Center for Translational Medicine (Shanghai)

      Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

      197 Ruijin Er Road, Shanghai, China, 200025

      Editor-in-Chief of Frontiers of Medicine