Identification of novelMECOMgene 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

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 (MDS1 and ectopic viral integration site 1 complex) 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.

Rare Hematologic Malignancies and Pre-Leukemic Entities in Children and Adolescents Young Adults

“…The translocation of t(3;21)(q26;q22) results in the fusion of MECOM with RUNX1 and has been reported in a pediatric patient with acute myelomonocytic leukemia [ 81 ], acute monoblastic leukemia [ 82 ], and secondary MDS/AML after treatment for T-cell ALL [ 83 ]. Additional MECOM fusions have been reported in pediatric patients, including MECOM-RPN1 in a patient with AML with megakaryocytic differentiation [ 84 ] and EIF4A2 - MECOM in a patient with severe congenital neutropenia and secondary AML [ 85 ]. Patients with these rare MECOM fusions ranged in age from 0 to 13 years.…”

Diagnosis and therapeutic decision-making for the neutropenic patient

“…55,56,[58][59][60] The rea son for reduced relapsed rates may be sec ond ary to the growth restraint on malig nant cells afforded by the germline defect, a fea ture reflected in some case reports of SCN patients with "indo lent" AML. 61 Although reported OS between myeloablation (MA) and reduced intensity con di tion ing (RIC) is sim i lar in SCN patients, myeloablative (MA) con di tion ing is recommended for patients with under ly ing malig nancy for elim i na tion of the malig nant clone.…”