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MCL1 as a therapeutic vulnerability in Burkitt lymphoma

Leukemia volume 37, pages 934–937 (2023)Cite this article

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Burkitt lymphoma (BL) is the most common non‐Hodgkin lymphoma (NHL, ~ 40%) in children and also occurs in adults [1]. It is characterized by MYC protein overexpression and a lack of BCL-2 protein expression [2]. The prognosis of BL has steadily improved over the past 30 years through the introduction of intensive chemotherapeutic regimens [3,4,5,6]. However, this success has come at the cost of significant chemotherapy-induced acute toxicity and long-term disability secondary to intensive chemotherapy. Furthermore, patients with BL who relapse or progress have chemotherapy-resistant disease that can rarely be salvaged [3,4,5].

The activation of MYC has been implicated in the promotion of aberrant cell proliferation [7,8,9] as well as replicative stress with concomitant DNA damage [7, 10,11,12]. These results suggest that BL uses alternative oncogenic signaling pathway(s) to counteract MYC-triggered apoptosis that are instrumental to guarantee BL survival. Here, we seek to selectively target the mechanisms counteracting MYC-triggered apoptosis and cell growth as a novel vulnerability for BL. We reported that MCL-1 plays an important role in BL cell survival and therapy response while counteracting MYC function, and is a new vulnerability for BL. Under selection pressure from MCL-1 inhibitor (MCL-1i), BL cells with high BCL-XL were selected. To this end, BCL-XL inhibition sensitized BL to MCL-1i in BL lines and a xenograft mouse model. Together, this study provides a rationale for using MCL-1 is as a promising anti-tumor strategy against BL and establishes MCL-1i-based combinations with targeted therapy as therapeutic strategies for these aggressive B-cell lymphomas.

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Fig. 1: MCL-1 is constitutively over-expressed and a key molecular therapeutic vulnerability for Burkitt lymphoma (BL) and a subset of large B-cell lymphomas.
Fig. 2: BCL-XL functions as a switch to govern MCL-1 inhibitor (MCL-1i) resistance ex vivo and in vivo.

Data availability

The datasets analyzed during the current study are available in the Gene Expression Omnibus repository under access numbers GSE10172 and GSE4475.

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Funding

This work was supported by funds from the Florida State Live Like Bella Pediatric Cancer Research Initiative.

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Author notes

  1. These authors contributed equally: Ren Yuan, Michelle Y. Wang.

  2. These authors jointly supervised this work: Xiaohong Zhao, Jianguo Tao.

Authors and Affiliations

  1. Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA

    Ren Yuan & Xiaohong Zhao

  2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    Michelle Y. Wang

  3. Department of Pathology, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Chengfeng Bi

  4. Department of Pathology, University of Virginia Medical Center, Charlottesville, VA, 22903, USA

    Jianguo Tao

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Contributions

RY was responsible for generating all CRISPR/cas9 cells and protein overexpressing cells, performing western blot experiments, and interpreting data. MYW was responsible for performing and analyzing image based cell viability assays in cell lines and patient samples, other cell viability assays, editing the manuscript. CB was responsible for providing patient samples and providing feedback on the study. XZ was responsible for study conception and design, performing cell viability experiments, the in vivo study, performing the analysis on the GEO patient datasets and editing the manuscript. JT was responsible for conception and design of the study, analyzing and interpreting all data, writing and reviewing the manuscript, and providing administrative, technical, and material support.

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Correspondence to Jianguo Tao.

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Yuan, R., Wang, M.Y., Bi, C. et al. MCL1 as a therapeutic vulnerability in Burkitt lymphoma. Leukemia 37, 934–937 (2023). https://doi.org/10.1038/s41375-023-01827-x

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