Flow cytometric expression of Bcl-2, Mcl-1, and their ratios correlates with primary and secondary cytogenetic changes and their combinations in multiple myeloma.
BH3 mimetics
Bcl-2
Biomarkers
Cytogenetics
Flow-cytometry
Mcl-1
Multiple myeloma
Journal
Annals of hematology
ISSN: 1432-0584
Titre abrégé: Ann Hematol
Pays: Germany
ID NLM: 9107334
Informations de publication
Date de publication:
12 Sep 2024
12 Sep 2024
Historique:
received:
05
08
2024
accepted:
08
09
2024
medline:
12
9
2024
pubmed:
12
9
2024
entrez:
12
9
2024
Statut:
aheadofprint
Résumé
Response to BH3 mimetics in multiple myeloma (MM) correlates with CCND1-rearrangement or expression of anti-apoptotic molecules, particularly Bcl-2 and Mcl-1. Our study investigates the relationship between cytogenetic abnormalities (CGAs) and intracellular Bcl-2 and Mcl-1 expression in myeloma plasma cells (MPCs) using flow cytometry (FCM). We measured median fluorescence intensity (MFI) of Bcl-2 and Mcl-1 in 163 bone marrow samples (143 MM, 20 controls) across various cell types. Both Bcl-2MFI and Mcl-1MFI were significantly higher in MPCs compared to other cells, with Bcl-2 MFI exceeding Mcl-1 MFI in MPCs. Bcl-2 expression peaked in CCND1-rearranged cases, while Mcl-1 expression was highest in cases with 1q21 gain/amplification. Notably, 65-74% of cases with other CGAs exhibited moderate to strong Bcl-2 or Mcl-1 expression, indicating potential utility of BH3 mimetics in this group, while 25% showed dim to absent expression of one or both markers, suggesting potential futility in these patients. Our study highlights FCM's potential for rapid Bcl-2 and Mcl-1 quantification, surpassing traditional methods. We propose that direct measurement of Bcl-2 and Mcl-1 expression in PCs by FCM, combined with cytogenetic characterization, could improve therapeutic decision-making regarding the use of BH3 mimetics in MM, potentially enhancing outcomes and overcoming resistance.
Identifiants
pubmed: 39264433
doi: 10.1007/s00277-024-06004-3
pii: 10.1007/s00277-024-06004-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L et al (2015) Revised International Staging System for multiple myeloma: a Report from International Myeloma Working Group. J Clin Oncol off J Am Soc Clin Oncol 33(26):2863–2869
doi: 10.1200/JCO.2015.61.2267
Slomp A, Peperzak V (2018) Role and regulation of pro-survival BCL-2 proteins in multiple myeloma. Front Oncol 8:533
doi: 10.3389/fonc.2018.00533
pubmed: 30524962
pmcid: 6256118
Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15(1):49–63
doi: 10.1038/nrm3722
pubmed: 24355989
Hanamura I (2021) Gain/Amplification of chromosome arm 1q21 in multiple myeloma. Cancers 13(2):256
doi: 10.3390/cancers13020256
pubmed: 33445467
pmcid: 7827173
Leverson JD, Zhang H, Chen J, Tahir SK, Phillips DC, Xue J et al (2015) Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis 6:e1590
doi: 10.1038/cddis.2014.561
pubmed: 25590800
pmcid: 4669759
Seiller C, Maiga S, Touzeau C, Bellanger C, Kervoëlen C, Descamps G et al (2020) Dual targeting of BCL2 and MCL1 rescues myeloma cells resistant to BCL2 and MCL1 inhibitors associated with the formation of BAX/BAK hetero-complexes. Cell Death Dis 11(5):1–14
doi: 10.1038/s41419-020-2505-1
Touzeau C, Dousset C, Le Gouill S, Sampath D, Leverson JD, Souers AJ et al (2014) The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia 28(1):210–212
doi: 10.1038/leu.2013.216
pubmed: 23860449
Nahi H, Kashif M, Klimkowska M, Karvouni M, Wallblom A, Gran C et al (2021) Low dose venetoclax as a single agent treatment of plasma cell malignancies harboring t(11;14). Am J Hematol 96(8):925–933
doi: 10.1002/ajh.26207
pubmed: 33901326
Harrison S, Cavo M, De La Rubia J, Popat R, Gasparetto C, Hungria VTM et al (2019) T(11;14) and high BCL2 expression are predictive biomarkers of response to Venetoclax in Combination with Bortezomib and Dexamethasone in patients with Relapsed/Refractory multiple myeloma: biomarker analyses from the phase 3 Bellini Study. Blood 134(Supplement1):142–142
doi: 10.1182/blood-2019-126094
Kumar S, Kaufman JL, Gasparetto C, Mikhael J, Vij R, Pegourie B et al (2017) Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood 130(22):2401–2409
doi: 10.1182/blood-2017-06-788786
pubmed: 29018077
Ross FM, Avet-Loiseau H, Ameye G, Gutiérrez NC, Liebisch P, O’Connor S et al (2012) Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica 97(8):1272–1277
doi: 10.3324/haematol.2011.056176
pubmed: 22371180
pmcid: 3409827
D’Agostino M, Cairns DA, Lahuerta JJ, Wester R, Bertsch U, Waage A et al (2022) Second revision of the International Staging System (R2-ISS) for overall survival in multiple myeloma: a European Myeloma Network (EMN) Report within the HARMONY Project. J Clin Oncol 40(29):3406–3418
doi: 10.1200/JCO.21.02614
pubmed: 35605179
Kumar SK, Harrison SJ, Cavo M, Rubia J, de la, Popat R, Gasparetto C et al (2020) Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 21(12):1630–1642
doi: 10.1016/S1470-2045(20)30525-8
pubmed: 33129376
Punnoose EA, Leverson JD, Peale F, Boghaert ER, Belmont LD, Tan N et al (2016) Expression Profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist Venetoclax in multiple myeloma models. Mol Cancer Ther 15(5):1132–1144
doi: 10.1158/1535-7163.MCT-15-0730
pubmed: 26939706
Flanagan L, Coughlan A, Cosgrove N, Roe A, Wang Y, Gilmore S et al (2024) Steroid-free combination of 5-azacytidine and venetoclax for the treatment of multiple myeloma. Haematologica
Gupta VA, Barwick BG, Matulis SM, Shirasaki R, Jaye DL, Keats JJ et al (2021) Venetoclax sensitivity in multiple myeloma is associated with B-cell gene expression. Blood 137(26):3604–3615
doi: 10.1182/blood.2020007899
pubmed: 33649772
pmcid: 8462405
Touzeau C, Ryan J, Guerriero J, Moreau P, Chonghaile TN, Le Gouill S et al (2016) BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics. Leukemia 30(3):761–764
doi: 10.1038/leu.2015.184
pubmed: 26174630
Matulis SM, Gupta VA, Neri P, Bahlis NJ, Maciag P, Leverson JD et al (2019) Functional profiling of venetoclax sensitivity can predict clinical response in multiple myeloma. Leukemia 33(5):1291–1296
doi: 10.1038/s41375-018-0374-8
pubmed: 30679802
pmcid: 6891824
Marschitz I, Tinhofer I, Hittmair A, Egle A, Kos M, Greil R (2000) Analysis of Bcl-2 protein expression in chronic lymphocytic leukemia. A comparison of three semiquantitation techniques. Am J Clin Pathol 113(2):219–229
doi: 10.1309/491W-L1TN-UFQX-T61B
pubmed: 10664624
Menendez P, Vargas A, Bueno C, Barrena S, Almeida J, De Santiago M et al (2004) Quantitative analysis of bcl-2 expression in normal and leukemic human B-cell differentiation. Leukemia 18(3):491–498
doi: 10.1038/sj.leu.2403231
pubmed: 14724650
Ludwig LM, Maxcy KL, LaBelle JL (2019) Flow Cytometry-based detection and analysis of BCL-2 family proteins and mitochondrial outer membrane permeabilization (MOMP). Methods Mol Biol Clifton NJ 1877:77–91
doi: 10.1007/978-1-4939-8861-7_5
Gautam A, Sreedharanunni S, Sachdeva MUS, Rana S, Kashyap D, Bose P et al (2021) The relative expression levels of CD148 and CD180 on clonal B cells and CD148/CD180 median fluorescence intensity ratios are useful in the characterization of mature B cell lymphoid neoplasms infiltrating blood and bone marrow - results from a single centre pilot study. Int J Lab Hematol 43(5):1123–1131
doi: 10.1111/ijlh.13467
pubmed: 33455071
Di Pasqua LG, Abdallah MM, Feletti F, Vairetti M, Ferrigno A (2024) Venetoclax-related Neutropenia in Leukemic patients: a Comprehensive Review of the underlying causes, risk factors, and management. Pharm Basel Switz 17(4):484
Miguel-García A, Orero T, Matutes E, Carbonell F, Miguel-Sosa A, Linares M et al (1998) bcl-2 expression in plasma cells from neoplastic gammopathies and reactive plasmacytosis: a comparative study. Haematologica 83(4):298–304
pubmed: 9592978
Puthier D, Pellat-Deceunynck C, Barillé S, Robillard N, Rapp MJ, Juge-Morineau N et al (1999) Differential expression of Bcl-2 in human plasma cell disorders according to proliferation status and malignancy. Leukemia 13(2):289–294
doi: 10.1038/sj.leu.2401302
pubmed: 10025904
Spaan I, van de Stolpe A, Raymakers RA, Peperzak V (2021) Multiple myeloma relapse is Associated with increased NFκB pathway activity and upregulation of the pro-survival BCL-2 protein BFL-1. Cancers 13(18):4668
doi: 10.3390/cancers13184668
pubmed: 34572895
pmcid: 8467450
Cleynen A, Samur M, Perrot A, Buisson L, Maheo S, Fulciniti M et al (2018) Variable BCL2/BCL2L1 ratio in multiple myeloma with t(11;14). Blood 132(26):2778–2780
doi: 10.1182/blood-2018-09-876433
pubmed: 30429160
pmcid: 6307986
Craig RW, Jabs EW, Zhou P, Kozopas KM, Hawkins AL, Rochelle JM et al (1994) Human and mouse chromosomal mapping of the myeloid cell leukemia-1 gene: MCL1 maps to human chromosome 1q21, a region that is frequently altered in preneoplastic and neoplastic disease. Genomics 23(2):457–463
doi: 10.1006/geno.1994.1523
pubmed: 7835896
Slomp A, Moesbergen LM, Gong J, nan, Cuenca M, von dem Borne PA, Sonneveld P et al (2019) Multiple myeloma with 1q21 amplification is highly sensitive to MCL-1 targeting. Blood Adv 3(24):4202–4214
doi: 10.1182/bloodadvances.2019000702
pubmed: 31856269
pmcid: 6929383
Terragna C, Poletti A, Solli V, Martello M, Zamagni E, Pantani L et al (2024) Multi-dimensional scaling techniques unveiled gain1q&loss13q co-occurrence in multiple myeloma patients with specific genomic, transcriptional and adverse clinical features. Nat Commun 15(1):1551
doi: 10.1038/s41467-024-45000-z
pubmed: 38378709
pmcid: 10879136