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

被引:9
作者
Abbas, Hussein A. [1 ]
Mohanty, Vakul [2 ]
Wang, Ruiping [3 ]
Huang, Yuefan [2 ,4 ]
Liang, Shaoheng [2 ,5 ]
Wang, Feng [3 ]
Zhang, Jianhua [3 ]
Qiu, Yihua [1 ]
Hu, Chenyue W. [1 ]
Qutub, Amina A. [6 ]
Dail, Monique [7 ]
Bolen, Christopher R. [8 ]
Daver, Naval [1 ]
Konopleva, Marina [1 ]
Futreal, Andrew [3 ]
Chen, Ken [2 ]
Wang, Linghua [3 ]
Kornblau, Steven M. [1 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA
[4] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Biostat & Data Sci, Houston, TX USA
[5] Rice Univ, Dept Comp Sci, Houston, TX USA
[6] Rice Univ, Dept Bioengn, Houston, TX USA
[7] Genentech Inc, Oncol Biomarker Dev, San Francisco, CA USA
[8] Genentech Inc, Oncol Bioinformat, San Francisco, CA USA
来源
FRONTIERS IN ONCOLOGY | 2021年 / 11卷
基金
美国国家卫生研究院;
关键词
acute myeloid leukemia; lineage; metabolism; inflammation; multiplatform analysis; SET ENRICHMENT ANALYSIS; EXPRESSION; MUTATIONS; CANCER; CELLS; MTOR; AML; ENCYCLOPEDIA; MALIGNANCIES; APOPTOSIS;
D O I
10.3389/fonc.2021.705627
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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页数:13
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