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

Öz

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.

Anahtar Kelimeler

• 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

Öz

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.

Anahtar Kelimeler

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

Kaynakça

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