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The lysine methyltransferase SMYD2 is required for normal lymphocyte development and survival of hematopoietic leukemias

Genes & Immunity volume 21, pages 119–130 (2020)Cite this article

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Abstract

The five membered SET and MYND Domain-containing lysine methyltransferase (SMYD) family plays pivotal roles in development and proliferation. Initially characterized within the cardiovascular system, one such member, SMYD2, has been implicated as an oncogene in leukemias deriving from flawed hematopoietic stem cell (HSC) differentiation. We show here that conditional SMYD2 loss disrupts hematopoiesis at and downstream of the HSC via both apoptotic loss and transcriptional deregulation of HSC proliferation and disruption of Wnt-β-Catenin signaling. Yet, previously documented SMYD2 cell cycle targets were unscathed. Turning our analysis to human leukemias, we observed that SMYD2 is highly expressed in CML, MLLr-B-ALL, AML, T-ALL, and B-ALL leukemias and its levels in B-ALL correlate with poor survival. SMYD2 knockdown results in apoptotic death and loss of anchorage-independent transformation of each of these hematopoietic leukemias. These data provide an underlying mechanism by which SMYD2 acts during normal hematopoiesis and as a proto-oncogene in leukemia.

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Fig. 1: Smyd2 conditional knockout (CKO) mice suffer significant losses in some, but not all, lineages downstream of the hematopoietic stem cell (HSC).
Fig. 2: Antibody (Ab) titers and isotype production are unaffected in Smyd2 CKO mice.
Fig. 3: SMYD2-deficient HSCs and downstream lineages undergo apoptosis.
Fig. 4: SMYD2 interacts with Frizzled Receptor 2 (FZD2) to regulate Wnt5a/3a, Stat3, and several STAT3 target genes critical for self-renewal of mouse HSCs.
Fig. 5: Meta-analyses of SMYD2 levels and survival in hematopoietic malignancies.
Fig. 6: SMYD2 knockdown in leukemias results in apoptosis, loss of viability, and reduction of growth.
Fig. 7: Expression of SMYD2 methylation targets are unaltered following loss of SMYD2 in leukemias.

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Acknowledgements

We thank M. Reth (Max-Planck Institute) for sharing Mb-1Cre mice. We thank June Harriss for her excellent contribution to all aspects of the animal husbandry, Chhaya Das and Maya Ghosh for help in cell culture and molecular techniques. We thank the Brown and Tucker laboratories for discussions and reading of the manuscript. Support for this work was provided by a Lymphoma Research Foundation Fellowship to JDD, NSF Grant 1060548 to MAB and NIH Grant R01CA31534, Cancer Prevention Research Institute of Texas (CPRIT) Grants RP100612, RP120348; and the Marie Betzner Morrow Centennial Endowment to HOT.

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  1. These authors contributed equally: Mark A. Brown, Melissa A. Edwards

Authors and Affiliations

  1. Department of Clinical Sciences, Colorado State University, Fort Collins, CO, 80523, USA

    Mark A. Brown

  2. Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, 80523, USA

    Mark A. Brown, Melissa A. Edwards & Ilham Alshiraihi

  3. Department of Molecular Biosciences, The University of Texas at Austin, 1 University Station A5000, Austin, TX, 78712, USA

    Melissa A. Edwards, Joseph D. Dekker & Haley O. Tucker

  4. Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA

    Huimin Geng

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MAB and HOT designed research; MAE, MAB, IA, HG, and JDD performed research; MAB, MAE, JDD, IA, and HOT analyzed data; MAB, MAE, and HOT wrote the paper.

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Correspondence to Haley O. Tucker.

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Brown, M.A., Edwards, M.A., Alshiraihi, I. et al. The lysine methyltransferase SMYD2 is required for normal lymphocyte development and survival of hematopoietic leukemias. Genes Immun 21, 119–130 (2020). https://doi.org/10.1038/s41435-020-0094-8

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