Decoupling Lineage-Associated Genes in Acute Myeloid Leukemia Reveals Inflammatory and Metabolic Signatures Associated With Outcomes

Hussein A. Abbas, Vakul Mohanty, Ruiping Wang, Yuefan Huang, Shaoheng Liang, Feng Wang, Jianhua Zhang, Yihua Qiu, Chenyue W. Hu, Amina A. Qutub, Monique Dail, Christopher R. Bolen, Naval Daver, Marina Konopleva, Andrew Futreal, Ken Chen, Linghua Wang, Steven M. Kornblau

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease with variable responses to therapy. Cytogenetic and genomic features are used to classify AML patients into prognostic and treatment groups. However, these molecular characteristics harbor significant patient-to-patient variability and do not fully account for AML heterogeneity. RNA-based classifications have also been applied in AML as an alternative approach, but transcriptomic grouping is strongly associated with AML morphologic lineages. We used a training cohort of newly diagnosed AML patients and conducted unsupervised RNA-based classification after excluding lineage-associated genes. We identified three AML patient groups that have distinct biological pathways associated with outcomes. Enrichment of inflammatory pathways and downregulation of HOX pathways were associated with improved outcomes, and this was validated in 2 independent cohorts. We also identified a group of AML patients who harbored high metabolic and mTOR pathway activity, and this was associated with worse clinical outcomes. Using a comprehensive reverse phase protein array, we identified higher mTOR protein expression in the highly metabolic group. We also identified a positive correlation between degree of resistance to venetoclax and mTOR activation in myeloid and lymphoid cell lines. Our approach of integrating RNA, protein, and genomic data uncovered lineage-independent AML patient groups that share biologic mechanisms and can inform outcomes independent of commonly used clinical and demographic variables; these groups could be used to guide therapeutic strategies.

Original languageEnglish (US)
Article number705627
JournalFrontiers in Oncology
Volume11
DOIs
StatePublished - Aug 4 2021

Keywords

  • acute myeloid leukemia
  • inflammation
  • lineage
  • metabolism
  • multiplatform analysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Functional Proteomics Reverse Phase Protein Array Core
  • Bioinformatics Shared Resource

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