Chronic Myelomonocytic Leukemia (CMML) is a myeloid neoplasm characterized by clinical features that overlap Myelodysplastic Syndromes (MDS) and Myeloproliferative Neoplasms (MPN) which culminate in a complex and aggressive natural history. The incidence of CMML is approximately 0.4 per 100 000, comparable to that seen in other adult leukemias. However, its prevalence is lower because the median overall survival is only 34 months and no therapies exist that augment this dismal natural history. Next generation sequencing technology has implicated epigenetic, splicing, and cytokine signaling pathways in the pathogenesis of CMML by annotating the frequencies of recurrent somatic gene mutations. Although this has allowed for the development of genetic murine model systems and uncovered potentially targetable vulnerabilities, current gene-based CMML models do not fully recapitulate the disease and no genomically-based therapy has been approved or is in clinical development. This project aims to address these issues using an alternative therapeutic concept and a novel approach for in vivo therapeutic credentialing. First, we have focused our preliminary data on identifying non-coding transcriptome aberrancies that may represent a therapeutic opportunity, rather than somatic gene mutations. These efforts have identified the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) as overexpressed and prognostic in CMML. Preliminary data presented here suggests that MALAT1 depletion may be a viable therapeutic strategy. To explore this further we will leverage CRISPR/CAS9 depleted and MALAT1 antisense oligonucleotide (ASO) treated (IONIS Pharmaceuticals) monocytic cell lines to formally credential MALAT1 depletion as a therapeutic strategy. Second, we will leverage a novel CMML patient-derived xenograft (PDX) model treated with clinical grade, MALAT1 depleting ASOs using 10 different primary CMML BMNC samples. Last, our preliminary data points to decreases in chemokine expression and NFkB activity as a mechanism by which MALAT1 depletion may augment CMML cell survival. This will be explored using reagents and techniques that have been optimized and/or are available in our laboratory. Taken together, this project is feasibly designed to provide preclinical data to support a novel MALAT1 ASO clinical trial in CMML.
The vast majority of our DNA contains elements that do not encode proteins yet all therapeutic targets for leukemia have focused solely on the protein-encoding component. This work seeks to determine whether one region of the non-coding DNA, known as MALAT1, could be leveraged as a therapeutic target in an aggressive type of leukemia known as Chronic Myelomonocytic Leukemia (CMML). Patients with CMML universally succumb to this lethal leukemia and are in dire need of disease-specific therapeutic options.