Systemic in vivo lentiviral delivery of miR-15a/16 reduces malignancy in the NZB de novo mouse model of chronic lymphocytic leukemia

Abstract

Similar to human CLL, the de novo NZB mouse model has a genetically determined age-associated increase in malignant B-1 clones and decreased expression of microRNAs miR-15a and miR-16 in B-1 cells. In the present study, lentiviral vectors were employed in vivo to restore miR-15a/16, and both the short-term single injection and long-term multiple injection effects of this delivery were observed in NZB. Control lentivirus without the mir-15a/16 sequence was used for comparison. We found that in vivo lentiviral delivery of mir-15a/16 increased miR-15a/16 expression in cells that were transduced (detected by GFP expression) and sera when compared to control lentivirus treatment. More importantly, mice treated with the miR- expressing lentivirus had decreased disease. The lentivirus had little systemic toxicity while preferentially targeting B-1 cells. Short-term effects on B-1 cells were direct effects and only malignant B-1 cells transduced with miR-15a/16 lentivirus had decreased viability. In contrast, long-term studies suggested both direct and indirect effects resulting from miR-15a/16 lentivirus treatment. A decrease in B-1 cells was found in both the transduced and non-transduced populations. Our data support the potential use of systemic lentiviral delivery of miR-15a/16 to ameliorate disease manifestations of CLL.

In vivo delivery of miRNAs for cancer therapy: Challenges and strategies

“…For example, lentiviral vectors expressing miR-15a/16 were systemic delivered into the de novo New Zealand Black (NZB) mouse model, a naturally occurring age-associated mouse model of chronic lymphocytic leukemia (CLL). Systemic lentiviral delivery of miR-15a/16 restored the expression of the targeted miRNAs and ameliorated disease manifestations of CLL [110]. In addition, miR-494, induced by tumor-derived factors such as TGF-β1, increases tumor accumulation and pro-angiogenesis and metastasis activity of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment.…”

Role of microRNA-15a in autoantibody production in interferon-augmented murine model of lupus

“…One of the mechanisms for this uncontrolled B-1 proliferation could be the partial loss of regulation of cyclin D1 by miR-15a/16 in B-1 cells as exogenous replacement of miR-15a/16 in malignant B-1 cells leads to cell cycle arrest, cyclin D1 decrease and apoptosis [62]. Overexpression of miR-15a/16 via lentiviral vectors in vivo in NZB mice lead to a significant decrease in malignant B-1 cells [64] and more interestingly, the anti-dsDNA autoantibodies were also increased (data not shown, manuscript in preparation). The findings that systemic in vivo elevation of miR-15a/16 in NZB lead to increased autoantibody levels is consistent with the findings in this present study in B/W.…”

“…In addition, evidence for preferential effects of miR-15a in B cell subsets comes from CLL patients and the mouse model of CLL, NZB mice, in which the germline deletion/mutation in mir-15a/16 loci caused underexpression of miR-15a/16 accompanied with only a B-1 malignant expansion [49, 73]. Moreover, the delivery of lentiviral miR-15a/16 in vivo in NZB mice only resulted in a malignant B-1 loss [64]. Thus, the intrinsic higher expression of miR-15a in splenic B-10 cells indicates that B-10 cell fate could be more dependent upon miR-15a effects than other B cell subsets.…”

Non-coding RNAs in cancer brain metastasis

“…The suppressive microRNA mimics are supposed to maintain the same biological function as endogenous microRNAs. This was proved both in vitro and in vivo as numerous researchers successfully restrained tumor progression with microRNA mimics (78, 79). Currently a microRNA mimic based drug MRX34 is under phase 1 clinical trial (NCT01829971).…”