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ACUTE MYELOID LEUKEMIA

UTX loss alters therapeutic responses in KMT2A-rearranged acute myeloid leukemia

Leukemia volume 37, pages 226–230 (2023)Cite this article

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Chromosomal rearrangements of the KMT2A or MLL gene (KMT2A-r) are found in ~10% acute myeloid leukemias (AML). KMT2A-r AML patients have a high rate of relapse and poor overall survival [1]. Recently, compounds targeting the MLL-fusion protein complex, such as DOT1L and Menin inhibitors, have shown promising preclinical efficacy [2]. However, molecular regulators of cellular response to these agents remain poorly understood. UTX (or KDM6A) is a histone H3K27 demethylase that plays a variety of roles in development and disease [3]. Recurrent loss-of-function UTX mutations have been found in many human cancers including leukemia [4]. Hematopoietic-specific loss of Utx in mouse induces spontaneous leukemia by regulating enhancer activity and chromatin remodeling [5]. UTX-null leukemia shows greater resistance to chemotherapy agents [6]. However, the impact of UTX on drug resistance of KMT2A-r AML has not been explored.

To further understand the drug resistance mechanism in leukemia cells with UTX loss, we performed transcriptome analysis in UTX wildtype and knockout OCI-AML2 cells treated with either DMSO or SGC0946. Principal component analysis shows that UTX knockout cells have a distinct transcriptional profile and were less responsive to DOT1L inhibitor treatment compared to UTX wildtype cells (Fig. 1K). Surprisingly, gene set variation analysis (GSVA) revealed that targets of MLL-fusion protein complex [9] were down-regulated by DOT1L inhibition in an equally effective way in both UTX wildtype and knockout cells (Fig. 1L). Indeed, we found that the canonical MLL-target genes, such as HOXA cluster genes, MEIS1, MEF2C, and PBX3 were consistently inhibited by SGC0946 in UTX knockout cells (Fig. 1M), suggesting that UTX loss-mediated resistance to DOT1L inhibition is independent of MLL-target genes. Consistent with previous studies [10], DOT1L inhibition resulted a robust increase of hematopoietic lineage development and myeloid cell differentiation genes (Fig. 1L). Interestingly, these genes were down-regulated after UTX depletion and failed to be activated by DOT1L inhibitor in UTX-deficient cells (Figs. 1L, M). An overview of differentially expressed genes regulated by DOT1L inhibitor also support a global reduction of DOT1L inhibition-mediated gene activation in UTX-null KMT2A-r AML cells (Fig. S3). These data suggest that UTX is required for DOT1L inhibitor-mediated up-regulation of myeloid differentiation gene programs.

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Fig. 1: UTX loss confers resistance to DOT1L inhibition in KMT2A-r AML.
Fig. 2: UTX loss downregulates BCL2A1 and sensitizes KMT2A-r AML to BCL2 inhibitor.

Data availability

The RNA-seq and ChIP-seq datasets have been deposited in the Gene Expression Omnibus (GEO) under the series number GSE214275.

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Acknowledgements

This work was supported in part by National Institutes of Health grants R01 CA259480, Concern Foundation, and Mark Foundation for Cancer Research. RL is an American Society of Hematology Scholar in Basic Science and a Research Scholar of American Cancer Society (RSG-22-036-01-DMC).

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, 35294, USA

    Xinyue Zhou, Pengcheng Zhang, Sajesan Aryal, Lixia Zhang & Rui Lu

  2. O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, 35294, USA

    Xinyue Zhou, Pengcheng Zhang, Sajesan Aryal, Lixia Zhang & Rui Lu

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Contributions

RL and XZ conceptualized the study and designed the experiments. XZ, PZ, SA, and LZ performed the experiments and interpreted the data. XZ and RL wrote the manuscript with inputs from all authors.

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Correspondence to Rui Lu.

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Zhou, X., Zhang, P., Aryal, S. et al. UTX loss alters therapeutic responses in KMT2A-rearranged acute myeloid leukemia. Leukemia 37, 226–230 (2023). https://doi.org/10.1038/s41375-022-01741-8

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