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MULTIPLE MYELOMA, GAMMOPATHIES

Role of MBD3-SOX2 axis in residual myeloma following pomalidomide

Leukemia volume 35, pages 3319–3323 (2021)Cite this article

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Combination therapies based on immune-modulatory drugs (IMiDsR) such as thalidomide, lenalidomide, and pomalidomide (Pom) have led to high rates of tumor regression in myeloma (MM) patients. These patients subsequently receive prolonged IMiD-based maintenance therapies. However, the great majority ultimately experience disease relapse, highlighting the unmet need to understand the mechanisms regulating the persistence and growth of residual myeloma. Binding of IMiDs such as Pom to the CRL4CRBN E3 ubiquitin ligase complex leads to proteasomal degradation of IKZF1 and (AIOLOS) IKZF3. Degradation of these targets is both necessary and sufficient for anti-proliferative effects of Pom on myeloma cells and also mediates immune-activation by enhancing IL2 expression in T cells [1,2,3,4,5]. However CRL4CRBN E3 ubiquitin-IKZF1/IKZF3 pathway does not explain the persistence of residual MM cells and apparent biological paradox that IMiDs mediate synergistic anti-myeloma effects with proteasome inhibitors in the clinic. Here we describe a novel MBD3-SOX2 pathway active in residual MM cells after Pom and its role in regulating growth and clonogenicity of residual MM following IMiD therapy and implications for IMiD-PI synergy.

In order to study the biology of residual MM following Pom, MM cells were exposed to the drug (100–300 ng/mL) or DMSO control in vitro and then utilized for subsequent experiments with indicated doses equivalent to the therapeutic concentrations achieved in vivo [6]. INA-6 cells xenografted into RGS6 mice [7] were utilized to study growth of MM cells in vivo using the intra-femoral delivery of MM cells as described earlier (Supplementary Fig. S1) [8]. Biospecimens obtained under the auspices of a clinical trial of pomalidomide (NCT01319422) in relapsed MM [9] were utilized to evaluate the effects of Pom on primary MM cells in vivo. All biospecimens were obtained following informed consent approved by Yale IRB and all animal studies were performed in accordance with protocols approved by Yale IACUC. Details of methods are noted under supplementary methods.

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Fig. 1: Enhanced clonogenic potential and growth of pomalidomide-residual disease is SOX2 dependent.
Fig. 2: MBD3 mediated SOX2 enrichment of human MM cells in Pom exposed residual MM cells.

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Acknowledgements

MVD is supported in part by funds from NCI R35 CA197603, Specialized Center for Research and translational research program of Leukemia and Lymphoma Society and the Multiple Myeloma Research Foundation (MMRF). Authors would like to thank patients and clinical colleagues at Yale, and Zifeng Mai, Lin Zhang, Dr. Mehmet H Kocoglu, Carla Weibel, Jon Alderman, Grzegorz Wylezinski, Dr. Roni Nowarski for their support.

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Authors and Affiliations

  1. Department of Medicine, Yale University, New Haven, CT, USA

    Rakesh Verma

  2. Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA

    Andrew R. Branagan

  3. Department of Pathology, Yale University, New Haven, CT, USA

    Mina L. Xu

  4. Department of Laboratory Medicine, Yale University, New Haven, CT, USA

    Mina L. Xu

  5. Department of Immunobiology, Yale University, New Haven, CT, USA

    Richard A. Flavell

  6. Howard Hughes Medical Institute, Yale University, New Haven, CT, USA

    Richard A. Flavell

  7. Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA

    Kavita M. Dhodapkar

  8. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Kavita M. Dhodapkar & Madhav V. Dhodapkar

  9. Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA

    Madhav V. Dhodapkar

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  1. Rakesh Verma
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Contributions

RV designed and performed experiments and wrote the manuscript. AB and KD performed clinical research and provided access to specimens. MLX provided help with immunohistochemical analyses. RAF provided access to mice used in the study. MVD provided oversight for the project and wrote manuscript. All authors contributed to interpretation of data and approved the final manuscript.

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Correspondence to Rakesh Verma or Madhav V. Dhodapkar.

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Verma, R., Branagan, A.R., Xu, M.L. et al. Role of MBD3-SOX2 axis in residual myeloma following pomalidomide. Leukemia 35, 3319–3323 (2021). https://doi.org/10.1038/s41375-021-01145-0

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