Abstract
Acute lymphoblastic leukaemia (ALL) is an aggressive haematological tumour driven by the malignant transformation and expansion of B-cell (B-ALL) or T-cell (T-ALL) progenitors. The evolution of T-ALL pathogenesis encompasses different master developmental pathways, including the main role played by Notch in cell fate choices during tissue differentiation. Recently, a growing body of evidence has highlighted epigenetic changes, particularly the altered expression of microRNAs (miRNAs), as a critical molecular mechanism to sustain T-ALL. The immune response is emerging as key factor in the complex multistep process of cancer but the role of miRNAs in anti-leukaemia response remains elusive. In this review we analyse the available literature on miRNAs as tuners of the immune response in T-ALL, focusing on their role in Natural Killer, T, T-regulatory and Myeloid-derived suppressor cells. A better understanding of this molecular crosstalk may provide the basis for the development of potential immunotherapeutic strategies in the leukemia field.
Highlights
Over the last 30 years, microRNAs have been the subject of much interest in molecular biology, both for clinical diagnostics and as therapeutic targets in human diseases.The role that the immune system plays in cancer is well established, as is the fact that miRNAs act as downstream and upstream modulators that activate important factors such as nuclear factor kappa-B (NF-κB), signal transducers and activators of transcription 3 (STAT3), tumour necrosis factor (TNF), and transforming growth factor β (TGFβ), which tune many immune cell functions [1]
More than 50% of patients with T-Acute lymphoblastic leukaemia (ALL) have NOTCH1 mutations and MYC has been identified as a key oncogenic mediator of NOTCH1 [63]
The crosstalk between notch homolog protein 1 (Notch1) and miR-19 is supported by the correlation between the high number of activating mutations in the Notch1 gene in more than 50% of leukaemia patients, and the high level of miR-19 in the same patients in T-cell ALL (T-ALL) [117]
Summary
Over the last 30 years, microRNAs (miRNAs) have been the subject of much interest in molecular biology, both for clinical diagnostics and as therapeutic targets in human diseases. Down-regulation represses the differentiation and accumulation of MDSCs by targeting MEF2C This table describes all the miRNAs that have been implicated in the immune response. Lymphoblastic Leukaemia (ALL), T-cell ALL (T-ALL); PD1: programmed death 1; PDL-1: programmed ligand death 1; DN: double negative; DP: double positive; SP: single positive; E2F1: E2F transcription factor 1; IL-2/IL6/IL-10/IL-16/IL-17: Interleukin 2/6/10/16/17; DNMT3a/b: DNA (cytosine-5)-methyltransferase 3a/b; cAMP: cyclic adenosine monophosphate; PKA: proteinase Kinase A; PTEN: phosphatase and tensin homolog; SHIP1: Src homology 2 (SH2) domain-containing inositol polyphosphate 50 -phosphatase 1; mTOR: mechanistic target of rapamycin; SOCS1: suppressor of cytokine signalling 1; SMAD7: small mother against decapentaplegic; TGF-β: transforming growth factor beta; FOXP3: forkhead box P3; CXCL12: C-X-C motif chemokine 12; BAG2: BCL-2associated athanogene; PRKD: protein kinase D; MEF2C: myocyte-specific enhancer factor 2C; IGF1: insulin-like growth factor 1
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