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Identification of Novel MECOM Gene Fusion and Personalized Therapeutic Targets Through Integrative Clinical Sequencing in Secondary Acute Myeloid Leukemia in a Patient with Severe Congenital Neutropenia: A Case Report and Literature Review.

Identification of Novel MECOM Gene Fusion and Personalized Therapeutic Targets Through Integrative Clinical Sequencing in Secondary Acute Myeloid Leukemia in a Patient with Severe Congenital Neutropenia: A Case Report and Literature Review.
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Connelly JA, Mody RJ, Wu YM, Robinson DR, Lonigro RJ, Vats P, Rabban E, Anderson B, Walkovich K,


Connelly JA, Mody RJ, Wu YM, Robinson DR, Lonigro RJ, Vats P, Rabban E, Anderson B, Walkovich K, (click to view)

Connelly JA, Mody RJ, Wu YM, Robinson DR, Lonigro RJ, Vats P, Rabban E, Anderson B, Walkovich K,

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Cold Spring Harbor molecular case studies 2018 03 23() pii 10.1101/mcs.a002204

Abstract

Severe congenital neutropenia (SCN) is a rare hematologic disorder characterized by defective myelopoiesis and a high incidence of malignant transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). SCN patients who develop MDS/AML have excessive toxicities to traditional chemotherapy and safer therapies are needed to improve overall survival in this population. In this report, we outline the use of a prospective integrative clinical sequencing trial (PEDS-MIONCOSEQ) in a patient with SCN and AML to help identify oncogenic targets for less toxic agents. Integrative sequencing identified two somatic cis-mutations in the colony stimulating factor 3 receptor (CSF3R) gene, a p.T640N mutation in the transmembrane region and a p.Q768* truncation mutation in the cytoplasmic domain. A somatic mutation p.H105Y, in the runt homology domain (RHD) of runt-related transcription factor 1 (RUNX1) was also identified. In addition, sequencing discovered a unique in-frame EIF4A2-MECOM chromosomal translocation with high MECOM expression. His mutations in CSF3R served as potential targets for tyrosine kinase inhibition and therefore provided an avenue to avoid more harmful therapy. This study highlights the utility of integrative clinical sequencing in SCN patients who develop leukemia and outlines a strategy on how to approach these patients in a future clinical sequencing trial to improve historically poor outcomes. A thorough review of leukemia in SCN and the role of CSF3R mutations in oncologic therapy are provided to support a new strategy on how to approach MDS/AML in SCN.

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