Page 231 - Haematologica Vol. 107 - September 2022

LETTER TO THE EDITOR
nolol significantly reduced MAFB expression in BTZ treated cells, underscoring the utility of using propranolol to target MAFB and overcome b adrenergic-stimulated ac- tivation of the AKT-mTOR axis (Figure 3A).
Since most chemo-resistance occurs because of impaired ability to execute apoptosis consequent to reduced “priming” i.e., suboptimal quantities of BH3 activators bound to anti-apoptotics,9,17,18 we evaluated the ex- pression of the major BCL-2 family proteins (Figure 3B). BTZ cytotoxicity is dependent upon increased NOXA ex- pression that, upon binding MCL-1, allows for pro-apop- totic BIM release. Interestingly, we found BTZ-induced elevation of NOXA and reduction of MCL-1 and BCL-xL is suppressed by isoproterenol (Figure 3A). Co-treatment with propranolol and BTZ maintains NOXA induction, MCL-1 suppression, and PARP cleavage with further re- duction of BCL-xL and PUMA. Lastly, we found propra- nolol increases sensitivity to the BCL-2 antagonist venetoclax (VEN) and importantly, isoproterenol stimu- lation did not reverse propranolol-induced sensitivity to VEN (Figure 3C).
In conclusion, our results suggest neurotransmitters elevate MAFB in MM CMP to augment pro-tumorigenic GMP-MDSC commitment, as summarized in the sche- matic (Figure 3D), that can be reversed with propranolol, restricting myelopoiesis in MM. Additionally, we show that b adrenergic stimuli selectively increase resistance to proteasome inhibitors, while targeting b adrenergic signaling with propranolol increases sensitivity to BTZ and VEN. We acknowledge the limited patient sample size for the current study and the need for greater mech- anistic understanding of how b adrenergic signals regu- late intra- and inter-cellular signaling to promote niche remodeling and drug sensitivity. Our results, in sum, underscore the importance of further interrogation of early application of propranolol and other b blockers in MM therapy.
Authors
Remya Nair,1,* Vimal Subramaniam,2,* Benjamin G. Barwick,1 Vikas A. Gupta,1 Shannon M. Matulis,1 Sagar Lonial,1 Lawrence H. Boise,1 Ajay K. Nooka,1 Kuzhali Muthumalaiappan2# and Mala Shanmugam1#
1Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA and 2Department of Surgery, Loyola University Medical Center, Maywood, Illinois and Burn and Shock Trauma Research Institute, Loyola University Chicago, Chicago, IL, USA
*RN and VS contributed equally as co-first authors. #KM and MS contributed equally as co-senior authors.
Correspondence:
M. SHANMUGAM - mala.shan@emory.edu
https://doi.org/10.3324/haematol.2022.280907
Received: February 23, 2022. Accepted: April 26, 2022. Prepublished: May 5, 2022.
©2022 Ferrata Storti Foundation Published under a CC BY-NC license
Disclosures
AKN has significant financial interest in Janssen Pharmaceuticals and has participated on advisory boards and received honoraria from Janssen, Takeda, Amgen, BMS/Celgene, Glaxo SmithKline, Sanofi, Oncopeptides, BeyondSpring, Karyopharm, SecuraBio, and Adaptive Technologies. SL is a consultant for Takeda, Celgene, Novartis, BMS, Amgen, ABBVIE, and Janssen and on the Board of directors with stock for TG therapeutics. LHB receives research funding from AstraZeneca (2019), consultancy, and honoraria from AstraZeneca; and performs consultancy for Genentech (2019) and Abbvie. All other authors declare no competing financial interests.
Contributions
RN, VS, KM, MS conceived and designed the research; RN and VS performed all experimentation; Bioinformatic analyses were performed by BGB. SMM and VAG assisted with patient sample purification; AKN, SL oversaw myeloma patient sample collection; LHB, BGB, VAG, AKN, SKM and KM provided helpful critiqu; KM provided edits to the manuscript; RN and MS wrote the manuscript.
Acknowledgments
We would like to thank Anthea Hammond, Ph.D., Emory University for editorial assistance.
Funding
This study was supported in part by NIH/NCI R01 CA208328 to MS, Leukemia Lymphoma Society TRP Award #6573-19 to MS and NIH/NIDDK 2R56DK097760 to KM and the Winship's Cancer Center Support Grant (P30CA138292) awarded by the National Cancer Institute of the National Institutes of Health.
Data-sharing statement
All technical information pertaining to the experimentation performed is available on request.
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