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

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dc.citation.articleNumber2897en_US
dc.citation.journalTitleFrontiers in Oncologyen_US
dc.citation.volumeNumber11en_US
dc.contributor.authorAbbas, Hussein A.en_US
dc.contributor.authorMohanty, Vakulen_US
dc.contributor.authorWang, Ruipingen_US
dc.contributor.authorHuang, Yuefanen_US
dc.contributor.authorLiang, Shaohengen_US
dc.contributor.authorWang, Fengen_US
dc.contributor.authorZhang, Jianhuaen_US
dc.contributor.authorQiu, Yihuaen_US
dc.contributor.authorHu, Chenyue W.en_US
dc.contributor.authorQutub, Amina A.en_US
dc.contributor.authorDail, Moniqueen_US
dc.contributor.authorBolen, Christopher R.en_US
dc.contributor.authorDaver, Navalen_US
dc.contributor.authorKonopleva, Marinaen_US
dc.contributor.authorFutreal, Andrewen_US
dc.contributor.authorChen, Kenen_US
dc.contributor.authorWang, Linghuaen_US
dc.contributor.authorKornblau, Steven M.en_US
dc.date.accessioned2021-09-21T15:37:52Zen_US
dc.date.available2021-09-21T15:37:52Zen_US
dc.date.issued2021en_US
dc.description.abstractAcute 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.en_US
dc.identifier.citationAbbas, Hussein A., Mohanty, Vakul, Wang, Ruiping, et al.. "Decoupling Lineage-Associated Genes in Acute Myeloid Leukemia Reveals Inflammatory and Metabolic Signatures Associated With Outcomes." <i>Frontiers in Oncology,</i> 11, (2021) Frontiers: https://doi.org/10.3389/fonc.2021.705627.en_US
dc.identifier.digitalfonc-11-705627en_US
dc.identifier.doihttps://doi.org/10.3389/fonc.2021.705627en_US
dc.identifier.urihttps://hdl.handle.net/1911/111388en_US
dc.language.isoengen_US
dc.publisherFrontiersen_US
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleDecoupling Lineage-Associated Genes in Acute Myeloid Leukemia Reveals Inflammatory and Metabolic Signatures Associated With Outcomesen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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