There is an urgent unmet medical need to identify environmentally-responsive non-coding RNA biomarkers to facilitate patient selection and therapeutic response evaluation in MPN clinical trials. MicroRNAs (miRNAs) are non-coding regulatory RNA molecules that represent an environmentally responsive class of biomarkers involved in cancer initiation and progression. While normal hematopoietic development is predicated on tight coordination of miRNA networks, deregulation of these networks occurs during MPN progression and TKI resistance. Also, primary (pri-) or precursor (pre-) miRNA A-to-I editing represents a source of epigenetic mutagenesis that may be responsible for broad transcriptional changes that drive LSC self-renewal and survival. However, edited miRNA profiles at various MPN stages have not been clearly elucidated. To date, MPN miRNA biomarker studies have focused on whole bone marrow rather than leukemia stem cells (LSC), which contribute to resistance and progression. In this proposal, we aim to identify a unique panel of ADAR1-edited miRNAs that predict MPN progression. We have successfully identified 179 downregulated miRNAs in normal CD34+ cells and 79 in chronic phase (CP) chronic myeloid leukemia progenitors that were transduced with lentiviral ADAR1. These ADAR-edited stem cell regulatory miRNAs were functionally clustered in self-renewal, cell cycle, and differentiation pathways. In parallel, we observed that the let-7 family of miRNAs was downregulated following wild-type ADAR1 transduction of normal progenitors. While we have identified edited miRNA signatures in CD34+ LSCs isolated from CML patients, we do not know whether these edited miRNA signatures predict progression and response to therapy in other MPN subtypes or in purified LSC populations. In this proposal, we will test whether edited miRNA signatures are able to 1) identify MPN patient progression in LSC isolated from both Ph+ and Ph- MPN patients and 2) to predict MPN treatment response by profiling edited miRNAs in MPN patients before and after therapy. With access to over 600 viably biobanked and clinically annotated samples in our laboratory, we will address the central hypotheses that ADAR1-edited miRNA signatures can be used as sensitive biomarkers of i) MPN progression and ii) therapeutic response.
Aim 1 : Identify edited miRNA signatures from CD34+ LSC in chronic phase Ph+ and Ph- MPN samples compared compared to advanced phase Ph+ and Ph- MPN patient samples.
Aim 2 : Proof of Principle: Dynamic identification of edited miRNA signature in LSC isolated from MPN patients before and after treatment.
We propose to address the potential of RNA editase ADAR1-mediated differential expression of edited microRNA as diagnostic and prognostic biomarkers for myeloproliferative neoplasm progression in ADAR-rich patient leukemia stem cells. The proposal will elucidate the expressional changes of microRNAs driven by A-to-I RNA editing mechanisms specific to leukemia stem cells and use such edited microRNA profile to predict patient therapeutic outcome.
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