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

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dc.citation.articleNumber2897
dc.citation.journalTitleFrontiers in Oncology
dc.citation.volumeNumber11
dc.contributor.authorAbbas, Hussein A.
dc.contributor.authorMohanty, Vakul
dc.contributor.authorWang, Ruiping
dc.contributor.authorHuang, Yuefan
dc.contributor.authorLiang, Shaoheng
dc.contributor.authorWang, Feng
dc.contributor.authorZhang, Jianhua
dc.contributor.authorQiu, Yihua
dc.contributor.authorHu, Chenyue W.
dc.contributor.authorQutub, Amina A.
dc.contributor.authorDail, Monique
dc.contributor.authorBolen, Christopher R.
dc.contributor.authorDaver, Naval
dc.contributor.authorKonopleva, Marina
dc.contributor.authorFutreal, Andrew
dc.contributor.authorChen, Ken
dc.contributor.authorWang, Linghua
dc.contributor.authorKornblau, Steven M.
dc.date.accessioned2021-09-21T15:37:52Z
dc.date.available2021-09-21T15:37:52Z
dc.date.issued2021
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.
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.
dc.identifier.digitalfonc-11-705627
dc.identifier.doihttps://doi.org/10.3389/fonc.2021.705627
dc.identifier.urihttps://hdl.handle.net/1911/111388
dc.language.isoeng
dc.publisherFrontiers
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.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleDecoupling Lineage-Associated Genes in Acute Myeloid Leukemia Reveals Inflammatory and Metabolic Signatures Associated With Outcomes
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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