Browsing by Author "Konopleva, Marina"

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    A mechanism for increased sensitivity of acute myeloid leukemia to mitotoxic drugs
    (Springer Nature, 2019) Panina, Svetlana B.; Baran, Natalia; da Costa, Fabio H.Brasil; Konopleva, Marina; Kirienko, Natalia V.
    Mitochondria play a central and multifunctional role in the progression of tumorigenesis. Although many recent studies have demonstrated correlations between mitochondrial function and genetic makeup or originating tissue, it remains unclear why some cancers are more susceptible to mitocans (anticancer drugs that target mitochondrial function to mediate part or all of their effect). Moreover, fundamental questions of efficacy and mechanism of action in various tumor types stubbornly remain. Here we demonstrate that cancer type is a significant predictor of tumor response to mitocan treatment, and that acute myeloid leukemias (AML) show an increased sensitivity to these drugs. We determined that AML cells display particular defects in mitochondrial metabolism that underlie their sensitivity to mitocan treatment. Furthermore, we demonstrated that combinatorial treatment with a mitocan (CCCP) and a glycolytic inhibitor (2-deoxyglucose) has substantial synergy in AML cells, including primary cells from patients with AML. Our results show that mitocans, either alone or in combination with a glycolytic inhibitor, display anti-leukemia effects in doses much lower than needed to induce toxicity against normal blood cells, indicating that mitochondria may be an effective and selective therapeutic target.
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    Decoupling Lineage-Associated Genes in Acute Myeloid Leukemia Reveals Inflammatory and Metabolic Signatures Associated With Outcomes
    (Frontiers, 2021) Abbas, Hussein A.; Mohanty, Vakul; Wang, Ruiping; Huang, Yuefan; Liang, Shaoheng; Wang, Feng; Zhang, Jianhua; Qiu, Yihua; Hu, Chenyue W.; Qutub, Amina A.; Dail, Monique; Bolen, Christopher R.; Daver, Naval; Konopleva, Marina; Futreal, Andrew; Chen, Ken; Wang, Linghua; Kornblau, Steven M.; Bioengineering
    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.