Coexisting Oncogenic Signaling Pathway Mutations in Cnl/Acml/CMML/MPN-U

Purpose:Chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), atypical myeloid leukemia (aCML), and unclassified myeloproliferative neoplasms (unMPN) are rare entities of myeloproliferative or myelodysplastic/myeloproliferative (MDS/MPN) syndromes. Due to poorly defined molecular mechanisms, these diseases have been, until now, diagnosed based on morphology and exclusionary criteria and treated empirically, resulting in dismal outcomes. Recent application of next generation sequencing has shed light on the genetic mechanisms of CNL/aCML/CMML/MPN-U. In particular, Maxson et al. and others have shown that CSF3R membrane proximal and transmembrane mutations are present in 83-89% of CNL and 3.3-44% of aCML patients, and expression of CSF3R membrane proximal mutants is sufficient to recapitulate the clinical features (mature granulocyte accumulation) of CNL in a mouse model. This has led to revision of the WHO diagnostic criteria for CNL, enabling a more accurate diagnosis and facilitating the development of targeted treatment for this disease. Aside from the CSF3R driver mutations, few recurrent signaling pathway mutations have been characterized in this group of diseases that could serve as the basis for such targeted therapeutic strategies. The aim of the current study is to characterize the frequency and distribution of signaling pathway driver mutations in a large cohort of CNL/aCML/CMML/MPN-U patients with the hope of informing diagnosis, prognosis and treatment.