TGF-β/SMAD Pathway Is Modulated by miR-26b-5p: Another Piece in the Puzzle of Chronic Lymphocytic Leukemia Progression

• Published in: Cancers 2022-03, Vol.14 (7), p.1676
• Main Authors: Marquez, Maria Elena, Sernbo, Sandra, Payque, Eugenia, Uria, Rita, Tosar, Juan Pablo, Querol, Juliana, Berca, Catalina, Uriepero, Angimar, Prieto, Daniel, Alvarez-Saravia, Diego, Oliver, Carolina, Irigoin, Victoria, Dos Santos, Gimena, Guillermo, Cecilia, Landoni, Ana Inés, Navarrete, Marcelo, Palacios, Florencia, Oppezzo, Pablo
• Format: Article
• Language: English
• Subjects: Apoptosis; c-Myc protein; CD5 antigen; Cell cycle; Cell death; Cell proliferation; Cell survival; Chronic lymphocytic leukemia; Clinical outcomes; Enzyme inhibitors; Epigenetics; Evolution; Flow cytometry; G1 phase; Homeostasis; Immunoregulation; Leukemia; Lymphatic leukemia; Lymphocytes B; Medical prognosis; Microenvironments; MicroRNAs; Myc protein; Neoplasia; Patients; Smad protein; Transforming growth factor-b; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14071676

Clinical and molecular heterogeneity are hallmarks of chronic lymphocytic leukemia (CLL), a neoplasm characterized by accumulation of mature and clonal long-lived CD5 + B-lymphocytes. Mutational status of the IgHV gene of leukemic clones is a powerful prognostic tool in CLL, and it is well established that unmutated CLLs (U-CLLs) have worse evolution than mutated cases. Nevertheless, progression and treatment requirement of patients can evolve independently from the mutational status. Microenvironment signaling or epigenetic changes partially explain this different behavior. Thus, we think that detailed characterization of the miRNAs landscape from patients with different clinical evolution could facilitate the understanding of this heterogeneity. Since miRNAs are key players in leukemia pathogenesis and evolution, we aim to better characterize different CLL behaviors by comparing the miRNome of clinically progressive U-CLLs vs. stable U-CLLs. Our data show up-regulation of miR-26b-5p, miR-106b-5p, and miR-142-5p in progressive cases and indicate a key role for miR-26b-5p during CLL progression. Specifically, up-regulation of miR-26b-5p in CLL cells blocks TGF-β/SMAD pathway by down-modulation of SMAD-4, resulting in lower expression of p21 kinase inhibitor and higher expression of c-Myc oncogene. This work describes a new molecular mechanism linking CLL progression with TGF-β modulation and proposes an alternative strategy to explore in CLL therapy.