Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal B cells arrested in G0/G1 stages that coexist, in different proportions, with proliferative B cells. Understanding the crosstalk between the proliferative subsets and their milieu could provide clues on CLL biology. We previously identified one of these subpopulations in the peripheral blood from unmutated patients that appears to be a hallmark of a progressive disease. Aiming to characterize the molecular mechanism underlying this proliferative behavior, we performed gene expression analysis comparing the global mRNA and microRNA expression of this leukemic subpopulation, and compared it with their quiescent counterparts. Our results suggest that proliferation of this fraction depend on microRNA-22 overexpression that induces phosphatase and tensin homolog downregulation and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B cells switches on PI3K/AKT, leading to downregulation of p27(-Kip1) and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40 ligand/interleukin-4 and, more importantly, that this regulatory loop is also present in lymph nodes from progressive unmutated patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide additional rationale for the usage of PI3K inhibitors.

Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia

“…miR-22 is postulated to play an important role in CLL proliferation by targeting phosphatase and tensin homolog (PTEN), resulting in activation of the PI3K/AKT pathway. 47,48 In our study, miR-22 was highly expressed in CLL cells in the LN, lower in circulating CLL cells, and even lower in circulating Bcells from healthy controls. Ibrutinib resulted in a 3-fold decrease in miR-22 expression in patients' CLL cells, which was accompanied by a concomitant increase in PTEN transcripts.…”

The Skewed Balance Between Tregs and Th17 in Chronic Lymphocytic Leukemia

“…Moreover, factors that interfere with PI3K/Akt pathway such as PD-1 inhibit Th17 differentiation and induce Treg phenotype [137]. However, as the stimulation of PI3K/Akt pathway stimulates the proliferative capacity of leukemic cells [138], it seems that blocking this pathway in order to expansion of Th17 cells may be rational. However, inhibition of this pathway may induce apoptosis in B-CLL cells [139].…”

Mir-22-3p Inhibits Arterial Smooth Muscle Cell Proliferation and Migration and Neointimal Hyperplasia by Targeting HMGB1 in Arteriosclerosis Obliterans

“…Accumulating amounts of evidence suggest that miR-22-3p partcipates mainly in cell growth and differentiation. Previous studies have shown that miR-22-3p can promote CLL-B cell and cardiomyocytes proliferation [26,27]; however, in most carcinomas, including breast cancer [28], gastric carcinoma [29], medulloblastomas [30] and liver cancer [31], miR-22-3p suppressed cancer cell proliferation. Thus the biological functions of miR-22-3p in HASMCs require further study.…”