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ACUTE MYELOID LEUKEMIA

Isocitrate dehydrogenase mutations are associated with altered IL-1β responses in acute myeloid leukemia

Leukemia volume 36, pages 923–934 (2022)Cite this article

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Abstract

Mutations in isocitrate dehydrogenase 2 (IDH2) have been noted to impact cellular differentiation in addition to DNA and histone methylation. However, little is known about the impact of IDH2 mutations on intracellular signaling. Using an isogenic cell line model, we investigated both differentiation and signaling responses in IDH2 mutant cells and show augmented responses to inflammatory immune ligands. Using phospho-specific flow and mass cytometry, we demonstrate IDH2 mutant cells were significantly more sensitive to IL-1β at multiple downstream readouts. Further, bulk RNA sequencing confirmed increases in cytokine-related signaling pathways and NF-κB target genes. Single-cell RNA sequencing of unstimulated and stimulated cells confirmed altered IL-1β transcriptional responses in the IDH2 mutant cells. Targeted inhibition of the IKK complex reduced IL-1β responses and induced cell death in primary IDH-mutated leukemia samples. Together, these results confirm altered IL-1β signaling in IDH2 mutant cells and identify this pathway as a potential therapeutic target.

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Fig. 1: IDH2R140Q induces alterations in immunophenotype that are  changed by enasidenib treatment.
Fig. 2: IDH2R140Q cells possess enhanced IL-1β-induced signaling responses.
Fig. 3: Bulk RNAseq identifies immune signaling changes in IDH2R140Q cells.
Fig. 4: scRNA-seq of IL-1β-stimulated cells confirms transcriptional NF-κB targets in IDH2R140Q compared to IDH2WT.
Fig. 5: Inhibition of the IKK complex blocks IL-1β signaling in both IDH2WT and IDH2R140Q cells.
Fig. 6: Inhibition of NF-κB in primary mIDH1/2 AML samples blocks IL-1β and TNFα signaling and induces apoptosis.
Fig. 7: Ex vivo treatment of IDH-mutated AML leads to shift in signaling profile and enrichment of primitive subsets.

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Data availability

RNA sequencing data are available in Gene Expression Omnibus (GEO) under accession number GSE186759 (Fig. 3) and GSE187777 (Fig. 4 and Supplementary Fig. 4). Mass cytometry data are available in flowrepository.org (ID FR-FCM-Z4M9 for data demonstrated in Fig. 1, Supplementary Fig. 1, Fig. 2A–D, and Supplementary Fig. 2A; ID FR-FCM-Z4MC for data demonstrated in Fig. 2E and Supplementary Fig. 2D; and ID FR-FCM-Z4MD for data demonstrated in Fig. 7) and all flow cytometry data are available upon request.

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Acknowledgements

This study was supported by NHLBI K23HL138291 (PBF), R01HL150078 (RSW), and 1PO1HL131477 (RSW), Vanderbilt Ingram Cancer Center. We acknowledge the support of the Vanderbilt Flow Cytometry Shared Resource and Creative Data Solutions Shared Resource, specifically J.P. Cartailler.

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Authors and Affiliations

  1. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Kathryn I. Sunthankar

  2. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Matthew T. Jenkins

  3. University of Kansas School of Medicine, Kansas City, Kansas, USA

    Candace H. Cote

  4. O’Neal Comprehensive Cancer Center, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Sweta B. Patel & Robert S. Welner

  5. Vanderbilt Ingram Cancer Center, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    P. Brent Ferrell

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Contributions

KIS and PBF conceived and designed the study. KIS, MTJ, CHC, and SBP collected the data presented. KIS, MTJ, RSW, and PBF analyzed and interpreted results. KIS and PBF prepared this manuscript. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to P. Brent Ferrell.

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PBF has received research funding from Incyte, Forma Therapeutics, and Astex Pharmaceuticals.

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Sunthankar, K.I., Jenkins, M.T., Cote, C.H. et al. Isocitrate dehydrogenase mutations are associated with altered IL-1β responses in acute myeloid leukemia. Leukemia 36, 923–934 (2022). https://doi.org/10.1038/s41375-021-01487-9

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