Galektin-3, prekürsör B-hücreli akut lenfoblastik lösemide ilaç direncini indükler

Abstract

β-galaktozid bağlayıcı protein ailesinin bir üyesi olan Galektin-3 (Gal-3), prekürsör B-hücreli akut lenfoblastik lösemi (pre-B ALL) hücreleri tarafından yüksek düzeyde ifade edilmekte ve salgılanmakta olup, bu durum ilaç direncine ve löseminin ilerlemesine yol açmaktadır. Tedavi direnci, akut lösemi ile ilişkili ölümlerin önde gelen nedenlerinden biri olmaya devam etmektedir. Kemik iliği mikroçevresindeki pre-B ALL hücreleri ile stromal hücreler arasındaki etkileşimler antineoplastik tedavi duyarlılığını engeller. Ortaya çıkan kanıtlar, kemik iliği mezenkimal stromal hücrelerinin (BM-MSC’ler) ekzosomlarda paketlenmiş veya çözünür bir protein olarak Gal-3 ürettiğini ve bunun pre-B ALL hücreleri tarafından içselleştirildikten sonra pre-B ALL hücrelerinde de novo endojen Gal-3 ekspresyonunun indüklenmesini desteklediğini göstermektedir. Ayrıca, pre-B ALL hücrelerinin antineoplastik ilaçları ile uzun süreli tedavisi de novo endojen Gal-3 ekspresyonunu indükler ve kemik iliği stromal hücreler tarafından indüklenen Gal-3 ekspresyonunu daha da artırır. Yüksek hücre içi Gal-3, pre-B ALL hücrelerinin hayatta kalmasını, hücre döngüsü ilerlemesini ve çoğalmasını uyarırken, yüksek hücre dışı Gal-3, pre-B ALL hücrelerinin kemik iliği stromal hücrelerine göçünü ve yapışmasını teşvik eder. Tüm bu süreçler ilaç direncine ve lösemi ilerlemesine katkıda bulunabilir. Bu derlemede, Gal-3’ün pre-B ALL hücrelerinde ilaç direncini nasıl desteklediğinin kritik moleküler yolları açıklanmakta ve bu da Gal-3’ü pre-B ALL hastalarında ilaç direncini ve hastalığın tekrarlamasını baskılamak için ideal bir aday hedef protein haline getirmektedir.

Keywords

• Galektin-3
• Prekürsör B-hücreli Akut Lenfoblastik Lösemi
• Mezenkimal stromal hücre; Ekzosom; İlaç direnci

Galectin-3 induces drug resistance in precursor B-cell acute lymphoblastic leukemia

Abstract

Galectin-3 (Gal-3), a member of the β-galactoside binding protein family, is highly expressed and secreted by precursor B cell acute lymphoblastic leukemia (pre-B ALL) cells, leading to drug resistance and leukemia progression. Treatment resistance remains a leading cause of death associated with acute leukemia. Interactions between pre-B ALL cells and stromal cells in the bone marrow microenvironment impede antineoplastic therapy sensitivity. Emerging evidence suggests that bone marrow mesenchymal stromal cells (BM-MSCs) produce Gal-3 as a protein packaged in exosomes or as a soluble protein, which promotes the induction of de novo endogenous Gal-3 expression in pre-B ALL cells after internalization by pre-B ALL cells. Furthermore, long-term treatment of pre-B ALL cells with antineoplastic drugs induces de novo endogenous Gal-3 expression and further increases Gal-3 expression induced by bone marrow stromal cells. High intracellular Gal-3 stimulates survival, cell cycle progression, and proliferation of pre-B ALL cells, whereas high extracellular Gal-3 promotes migration and adhesion of pre-B ALL cells to bone marrow stromal cells. All of these processes may contribute to drug resistance and leukemia progression. This review describes the critical molecular pathways of how Gal-3 promotes drug resistance in pre-B ALL cells, making Gal-3 an ideal candidate target protein to suppress drug resistance and disease relapse in pre-B ALL patients.

Keywords

• Galectin-3
• Precursor B-cell Acute Lymphoblastic Leukemia
• Mesenchymal stromal cell; Exosome; Drug resistance.

References

1. 1.Dander E, Palmi C, D’Amico G, et al. The BoneMarrow Niche in B-Cell Acute LymphoblasticLeukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia. Int J Mol Sci 2021;22(9): 4426.
2. 2.Sun W, Malvar J, Sposto R, et al. Outcome ofchildren with multiply relapsed B-cell acutelymphoblastic leukemia: a therapeutic advances inchildhood leukemia & lymphoma study. Leukemia2018; 32(11): 2316–25.
3. 3.Yu K, Wang J, Lu T, et al. Overexpression of hemeoxygenase‐1 in microenvironment mediatesvincristine resistance of B‐cell acute lymphoblasticleukemia by promoting vascular endothelial growthfactor secretion. J Cell Biochem 2019; 120(10):17791–810.
4. 4.Stock W. Current treatment options for adultpatients with Philadelphia chromosome-positiveacute lymphoblastic leukemia. Leuk Lymphoma2010; 51(2): 188–98.
5. 5.Pui C-H, Evans WE. Treatment of acutelymphoblastic leukemia. N Engl J Med 2006; 354(2):166–78.
6. 6.Housman G, Byler S, Heerboth S, et al. DrugResistance in Cancer: An Overview. Cancers (Basel)2014; 6(3): 1769–92.
7. 7.Jędraszek K, Malczewska M, Parysek-Wójcik K, etal. Resistance Mechanisms in Pediatric B-Cell AcuteLymphoblastic Leukemia. Int J Mol Sci 2022; 23(6):3067.
8. 8.Mengxuan S, Fen Z, Runming J. Novel Treatmentsfor Pediatric Relapsed or Refractory Acute B-CellLineage Lymphoblastic Leukemia: PrecisionMedicine Era. Front Pediatr 2022; 10: 923419.

9. 9.Nguyen K, Devidas M, Cheng SC, et al. Factorsinfluencing survival after relapse from acutelymphoblastic leukemia: a Children’s OncologyGroup study. Leukemia 2008; 22(12): 2142–50.
10. 10.Manabe A, Coustan-Smith E, Behm F, et al. Bonemarrow-derived stromal cells prevent apoptotic celldeath in B- lineage acute lymphoblastic leukemia. Blood 1992; 79(9): 2370–7.
11. 11.Ayala F, Dewar R, Kieran M, et al. Contribution ofbone microenvironment to leukemogenesis andleukemia progression. Leukemia 2009; 23(12):2233–41.
12. 12.Zhang B, Groffen J, Heisterkamp N. Increasedresistance to a farnesyltransferase inhibitor by N-cadherin expression in Bcr/Abl-P190 lymphoblasticleukemia cells. Leukemia 2007; 21(6): 1189–97.
13. 13.Chou FC, Chen HY, Kuo CC, et al. Role of Galectinsin Tumors and in Clinical Immunotherapy. Int J MolSci 2018; 19(2): 430.
14. 14. Wang L, Guo XL. Molecular regulation of galectin-3 expression and therapeutic implication in cancerprogression. Biomedicine & Pharmacotherapy2016; 78: 165–71.
15. 15.Funasaka T, Raz A, Nangia-Makker P. Nucleartransport of galectin-3 and its therapeuticimplications. Semin Cancer Biol 2014; 27: 30–8.
16. 16.Ahmed R, Anam K, Ahmed H. Development ofGalectin-3 Targeting Drugs for TherapeuticApplications in Various Diseases. Int J Mol Sci 2023;24(9): 8116.
17. 17.Cheng CL, Hou HA, Lee MC, et al. Higher bonemarrow LGALS3 expression is an independentunfavorable prognostic factor for overall survival inpatients with acute myeloid leukemia. Blood 2013;121(16): 3172-80.
18. 18.Fei F, Abdel-Azim H, Lim M, et al. Galectin-3 inpre-B acute lymphoblastic leukemia. Leukemia2013; 27(12): 2385–8.
19. 19.Yamamoto-Sugitani M, Kuroda J, Ashihara E, etal. Galectin-3 (Gal-3) induced by leukemiamicroenvironment promotes drug resistance andbone marrow lodgment in chronic myelogenousleukemia. Proc Natl Acad Sci U S A 2011; 108(42):17468–73.
20. 20.Fei F, Joo EJ, Tarighat SS, et al. B-cell precursoracute lymphoblastic leukemia and stromal cellscommunicate through Galectin-3. Oncotarget 2015;6(13): 11378–94.
21. 21.Tarighat SS, Fei F, Joo EJ, et al. OvercomingMicroenvironment-Mediated Chemoprotectionthrough Stromal Galectin-3 Inhibition in AcuteLymphoblastic Leukemia. Int J Mol Sci 2021; 22(22):12167.
22. 22.Feldhahn N, Arutyunyan A, Stoddart S, et al.Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia.Oncoimmunology 2012; 1(5): 618–629.
23. 23.Yoshii T, Fukumori T, Honjo Y, et al. Galectin-3Phosphorylation Is Required for Its Anti-apoptoticFunction and Cell Cycle Arrest. Journal of BiologicalChemistry 2002; 277(9): 6852–7.
24. 24.Takenaka Y, Fukumori T, Yoshii T, et al. Nuclearexport of phosphorylated galectin-3 regulates itsantiapoptotic activity in response tochemotherapeutic drugs. Mol Cell Biol 2004; 24(10):4395–406.
25. 25. Tabe Y, Konopleva M. Advances in understandingthe leukaemia microenvironment. Br J Haematol2014; 164(6): 767–78.
26. 26.Azizidoost S, Babashah S, Rahim F, et al. Bonemarrow neoplastic niche in leukemia. Hematology2014; 19(4): 232–8.
27. 27.Yıldırım C. Galectin-3 Release in the BoneMarrow Microenvironment Promotes DrugResistance and Relapse in Acute Myeloid Leukemia.Life 2025; 15(6): 937.
28. 28.Hu K, Gu Y, Lou L, et al. Galectin-3 mediates bonemarrow microenvironment-induced drugresistance in acute leukemia cells via Wnt/β-cateninsignaling pathway. J Hematol Oncol 2015; 8(1): 1.
29. 29.Song S, Mazurek N, Liu C, et al. Galectin-3Mediates Nuclear β-Catenin Accumulation and WntSignaling in Human Colon Cancer Cells byRegulation of Glycogen Synthase Kinase-3β Activity.Cancer Res 2009; 69(4): 1343–9.
30. 30. Kobayashi T, Shimura T, Yajima T, et al. Transientgene silencing of galectin‐3 suppresses pancreaticcancer cell migration and invasion throughdegradation of β‐catenin. Int J Cancer 2011;129(12): 2775–86.
31. 31. Luis TC, Ichii M, Brugman MH, et al. Wnt signaling strength regulates normal hematopoiesis and itsderegulation is involved in leukemia development. Leukemia 2012; 26(3): 414–21.
32. 32.Kuek V, Hughes AM, Kotecha RS, et al.Therapeutic Targeting of the LeukaemiaMicroenvironment. Int J Mol Sci 2021; 22(13): 6888.
33. 33.Kumar B, Garcia M, Weng L, et al. Acute myeloidleukemia transforms the bone marrow niche into aleukemia-permissive microenvironment throughexosome secretion. Leukemia 2018; 32(3): 575–87.
34. 34.Hsu DK, Chen HY, Liu FT. Galectin-3 regulates T-cell functions. Immunol Rev 2009; 230(1): 114–27.
35. 35. Balan V, Nangia-Makker P, Jung YS, et al. Galectin-3: A novel substrate for c-Abl kinase. Biochimica etBiophysica Acta (BBA) - Molecular Cell Research2010; 1803(10): 1198–205.
36. 36.Fei F, Zhang M, Tarighat SS, et al. Galectin-1 andGalectin-3 in B-Cell Precursor Acute LymphoblasticLeukemia. Int J Mol Sci 2022; 23(22): 14359.
37. 37.Dumic J, Dabelic S, Flögel M. Galectin-3: an open-ended story. Biochim Biophys Acta 2006; 1760(4):616–35.
38. 38.Haudek KC, Spronk KJ, Voss PG, et al. Dynamicsof galectin-3 in the nucleus and cytoplasm.Biochimica et Biophysica Acta (BBA) - GeneralSubjects 2010; 1800(2): 181–9.
39. 39.Choi S, Henderson MJ, Kwan E, et al. Relapse inchildren with acute lymphoblastic leukemiainvolving selection of a preexisting drug-resistantsubclone. Blood 2007; 110(2): 632–9.
40. 40.Chiarini F, Lonetti A, Evangelisti C, et al.Advances in understanding the acute lymphoblasticleukemia bone marrow microenvironment: From biology to therapeutic targeting. Biochim Biophys Acta 2016; 1863(3): 449–63.
41. 41.Yeoh AEJ, Li Z, Dong D, et al. Effective ResponseMetric: a novel tool to predict relapse in childhoodacute lymphoblastic leukaemia using time-seriesgene expression profiling. Br J Haematol 2018;181(5): 653–63.
42. 42.Fortuna-Costa A, Gomes AM, Kozlowski EO, et al.Extracellular Galectin-3 in Tumor Progression andMetastasis. Front Oncol 2014; 4: 138.
43. 43.Gao X, Balan V, Tai G, et al. Galectin-3 induces cellmigration via a calcium-sensitive MAPK/ERK1/2pathway. Oncotarget 2014; 5(8): 2077–84.
44. 44.Bum-Erdene K, Collins PM, Hugo MW, et al. NovelSelective Galectin-3 Antagonists Are Cytotoxic toAcute Lymphoblastic Leukemia. J Med Chem 2022;65(8): 5975–89.
45. 45.Fallati A, Di Marzo N, D’Amico G, et al.Mesenchymal Stromal Cells (MSCs): An Ally of B-CellAcute Lymphoblastic Leukemia (B-ALL) Cells inDisease Maintenance and Progression within theBone Marrow Hematopoietic Niche. Cancers (Basel)2022; 14(14): 3303.