Page 230 - Haematologica Vol. 107 - September 2022

LETTER TO THE EDITOR AB
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Figure 3. Propranolol increases sensitivity to the BCL-2 antagonist venetoclax. (A and B) L363 cells treated with bortezomib (BTZ) and/or isoproterenol (ISO)/propranolol (PRO) as indicated for 18 hours (h), assessed for indicated proteins by immunoblot analyses. (C) Cell lines treated with 75 mM PRO or 75 mM ISO in combination with 0.01 mM venetoclaX (VEN) for 24 h assessed for viability. All cell death/viability assessed by AnnexinV/DAPI flow cytometry. (D) Model: b adrenergic signaling elevates MAFB vs. GATA1 expression in common myeloid progenitors (CMP) leading to increased granulocyte monocyte progenitor (GMP) vs. megakaryocyte erythrocyte progenitor (MEP) specification in multiple myeloma, establishing a feed forward loop. Model is created in BioRender.com. MDSC: myeloid-derived suppressor cells; HSPC: hematopoietic stem and progenitor cells; bAR: b adrenergic receptor.
juxtapose the IgH enhancer to drive elevated levels of MAFB and MAF expression, respectively (Figure 2C and D). ADRB1 and ADRB3 expression was low to undetectable in most MM samples (data not shown). Additionally, ADRB2 was detected in all MM cell lines tested (Online Supple- mentary Figure S1F). These observations prompted us to examine the effects of propranolol on MM cells. Propranolol has potent anti-cancer effects attributed to both tumor intrinsic and extrinsic effects.15 We found pro- pranolol to elicit cytotoxicity in MM cell lines (Figure 2E). Proteasome inhibitors (PI) like bortezomib (BTZ) are back- bone MM therapeutics, however, most MM patients be-
come refractory to PI. We found treatment of MM cell lines with lower doses of propranolol enhanced, while isopro- terenol reversed, sensitivity to BTZ, irrespective of MAFB expression status (Figure 2F). In order to clinically validate our observations, we tested the effects of isoproterenol, propranolol and BTZ treatments in MM patient samples (n=4). As seen in cell lines, isoproterenol promoted resis- tance to BTZ, while isoproterenol increased sensitivity to BTZ in the MM primary cells (Figure 2G). We found isopro- terenol in the context of BTZ treatment to elevate MAFB, pAKT, p-S6 and pmTORC1 (Figure 3A). While treatment with BTZ is known to stabilize MAFB expression,16 propra-
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