Abstract 2452: Detailed genomic characterization of CNL/aCML/MPN-U/CMML reveals disease subgroups that may benefit from rationally-designed combination therapies
Authors: Zhang Haijiao , Wilmot Beth , Bottomly Daniel , White Libbey , Segerdell Erik , McWeeney Shannon K. , Khanna Vishesh , Rofelty Angela , Means Sophie , Junio Brian , Savage Samantha , Stevens Emily , Dao Kim-Hien , Maxson Julia E. , Tyner Jeffrey W. 
Published: July 2017

Abstract
Purpose: Chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), and unclassified myeloproliferative neoplasms (MPN-U) are a group of heterogeneous disorders belonging to rare entities of myeloproliferative or myelodysplastic/myeloproliferative (MDS/MPN) syndromes. Due to lack of specific molecular markers and the limited understanding of pathogenesis, the treatment of these diseases remains empirical, resulting in poor outcomes. Recently, recurrent mutations in ASXL1, TET2, SRSF2 and cell signaling genes have been identified in these diseases. In this study we aim to analyze the co-occurrence patterns of these gene mutations, as well as the association of different mutations with disease subtypes and treatment outcomes.
Methods and results: We performed whole exome sequence and RNA-Seq on primary patient samples. Consistent with previous studies, high frequencies of ASXL1, SRSF2, TET2, SETBP1 and signaling pathway mutations were observed; whereas mutations of MPL, CEBPa, IDH1/2, and TP53 were rare. Further variant allelic frequency analysis demonstrated that mutations of the chromatin modifiers, epigenetic markers and splicing factors are mostly present in the major clones indicating early acquisition of these mutations. In addition, ASXL1/2, splicing factor and signaling pathway mutations co-occur in around 45% of all patients with these mutations, indicating that they drive these diseases in a cooperative manner.
RNA-seq analysis demonstrated two major gene expression clusters with high levels of either RAS or JAK-STAT signaling alterations respectively, indicating a potential need for distinct therapeutic targeting of specific subgroups of these diseases. In addition, we observed that 17% of patients have more than one signaling pathway mutation, possibly in distinct subclones, providing rationale for drug combination treatment.
Furthermore, we observed that mutations related to RAS signaling pathway are prevalent in CMML; CSF3R and JAK2 mutations are enriched in CNL; whereas, RAS and JAK-STAT pathway double mutations are more frequent in aCML. Similar incidence of ASXL1, splicing factor and epidemics mutations are observed across all these diseases.
Conclusions: CNL/aCML/MPN-U/CMML is a group of heterogeneous diseases associated with chromatin modifier, epigenetic, splicing factor and signaling pathway mutations in concomitant manner. We propose future studies of rational drug combinations with agents, targeting epigenetic and splicing factors, together with the appropriate signaling pathway inhibitors. Our study represents a large-scale comprehensive genomic analysis of these diseases, which reveals novel insight into patterns of mutation co-occurrence which could translate into new treatment paradigms for these difficult to treat hematologic malignancies.
Citation Format: Haijiao Zhang, Beth Wilmot, Daniel Bottomly, Libbey White, Erik Segerdell, Shannon K. McWeeney, Vishesh Khanna, Angela Rofelty, Sophie Means, Brian Junio, Samantha Savage, Emily Stevens, Kim-Hien Dao, Julia E. Maxson, Jeffrey W. Tyner. Detailed genomic characterization of CNL/aCML/MPN-U/CMML reveals disease subgroups that may benefit from rationally-designed combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2452. doi:10.1158/1538-7445.AM2017-2452