hsa-mir183/EGR1–mediated regulation of E2F1 is required for CML stem/progenitor cell survival

Abstract

Chronic myeloid leukemia (CML) stem/progenitor cells (SPCs) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPCs maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase-dependent pathway mediated by the upregulation of , the downregulation of its direct target early growth response 1 (EGR1), and, as a consequence, upregulation of E2F1. We show here that inhibition of reduced proliferation and impaired colony formation of CML SPCs. Downstream of this, inhibition of also reduced proliferation of CML SPCs, leading to p53-mediated apoptosis. In addition, we demonstrate that E2F1 plays a pivotal role in regulating CML SPC proliferation status. Thus, for the first time, we highlight the mechanism of/EGR1-mediated E2F1 regulation and demonstrate this axis as a novel, critical factor for CML SPC survival, offering new insights into leukemic stem cell eradication.

Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells

“…demonstrated that the integrated stress response and the transcription factor ATF4 is involved in AML cell proliferation and is uniquely active in HSCs and LSCs (van Galen et al, 2018;Heydt et al, 2018 CCND2, CDC25A, PLK1, CENPO, AURKB) and of the E2F1 gene signature that were also identified after CALCRL knockdown. Recently, it has been proposed that E2F1 plays a pivotal role in regulating CML stem/progenitor cells proliferation and survival status (Pellicano et al, 2018). Several signaling pathways, for instance MAPKs, CDK/cyclin or PI3K/AKT, have been described to be stimulated by ADM/CALCRL axis and may control pRB/E2F1 complex activity (Hallstrom et al, 2008;Wang et al, 1998).…”

Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions

“…Although other miRNAs regulating LSC survival or qLSC reentry into cycle have been associated with CML development (18,49,50), to our knowledge, MIR300 is the only cell…”

“…However, hypoxia-induced TGFBR1/2 upregulation in CML LSCs (36) may also contribute to increased TUG1 expression and regulation of MIR300 functions. Hypoxiainduced TUG1 expression in CML qLSCs may also depend on Notch activity (58); however, blocking TGFβ1 signaling in CD34 + CML progenitors and hypoxia-exposed qLSCs also strongly suppressed expression of FoxM1, a TUG1 transcriptional inducer and regulator of CML LSC quiescence and cycling activity (37,39,50). Thus, hypoxia-TGFβ-FoxM1, but not Notch-induced signals, increases TUG1 expression in CML LSCs to selectively inhibit MIR300 PP2A-mediated proapoptotic function while allowing MIR300-dependent entry into quiescence.…”

Killing the minotaur in its amazing maze

“…Although a combination of ibrutinib and venetoclax can induce U-MRD in up to 69% of patients based on flow cytometry (U-MRD4), NGS-based assays might even better guide us in the future to define the subpopulation of patients with residual disease that would benefit from a prolonged combination therapy or an extended maintenance phase. 6 Similar MRD-tailored treatment concepts in the frontline and relapsed setting have been introduced also by other research groups. 7,8 The better and more sensitive our MRD detection tool is, the better and more precise our treatment strategy will be for the individual patient with CLL.…”