Dissecting chronic lymphocytic leukemia microenvironment signals in patients with unmutated disease: microRNA-22 regulates phosphatase and tensin homolog/AKT/FOXO1 pathway in proliferative leukemic cells

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells arrested in G0/G1 stages that coexist with proliferative B cells. We identified one of these proliferative subsets in the peripheral blood from patients with unmutated disease (UM). Aiming to characterize the molecular mechanism underlying this proliferative behavior, we performed gene expression analysis of the mRNA and microRNAs in this leukemic subpopulation and compared results with those for the quiescent counterpart. Our results suggest that proliferation of this subset mainly depends on microRNA-22 overexpression, which induces phosphatase and tensin homolog (PTEN) down-regulation and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. These results underline the role of the PI3K/AKT pathway at the origin of this proliferative pool in patients with UM CLL and provide additional rationale for the use 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.…”

Ibrutinib therapy downregulates AID enzyme and proliferative fractions in chronic lymphocytic leukemia

“…Taking into account different studies demonstrating the importance of PI3K/AKT signaling during CLL progression, 23,31,33,34 we analyzed the phosphorylation status of the AKT/PKB pathway during ibrutinib treatment. To accomplish this task, we isolated the CXCR4 low CD5 high PF from patients CLL3, CLL16, and CLL36 by cell sorting before and during ibrutinib treatment, and analyzed these samples using a phospho-array platform.…”

Deciphering the roles of FOXO1 in human neoplasms

“…discovered that Pre‐BCR signaling activates the FOXO1 pathway and inhibits the development of B‐ALL, indicating FOXO1 as an antitumor molecule in leukemia . FOXO1 inhibits the proliferation of cancer cells in chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML), thereby exerting antitumor actions in hematologic neoplasms. Curcumin, a well‐known bioactive compound derived from turmeric, potentiates antitumor activity of L‐asparaginase via activation of FOXO1 and inhibition of Akt signaling in ALL, which is concomitant with enhanced apoptosis and suppressed proliferation of leukemia cells …”