Clonal Mutations and Clonal Hierarchy in Pediatric Myeloid Neoplasms
Authors: Niemeyer Charlotte Marie , Wlodarski Marcin W 
Published: October 2019

Abstract
Pediatric myeloid neoplasms are a clinically and genetically heterogeneous group of clonal diseases. Unlike in adults inherited predisposition plays a major role in leukemogenesis. A number of germline mutations are known to increase the risk of somatically occurring myeloid transformation. These include the genes associated with the classical inherited bone marrow failure syndromes, but also transcriptopathies resulting from RUNX1, CEBPA or GATA2 deficiency. Herein we review the most significant findings from recent years and our present experience on the clonal landscape of myeloid malignancies in children with a focus on pediatric MDS and JMML. In both disease entities, monosomy 7 is the most frequent chromosomal aberration. It is likely that haploinsufficiency of genes located on chromosome 7 contributes to clonal evolution. Several of the more than 1000 lost genes were postulated as mechanistic drivers. However, in most cases additional somatic mutations not related to chromosome 7 are found at diagnosis, making it difficult to pinpoint the initial oncogenic hit. Driver somatic hits frequently encountered in adults with MDS, affecting TET2, DNMT3A or the spliceosome genes, do not play a major role in the pathogenesis of childhood disease. Also, considering the young age, environmental effects and age-related pre-malignant clonal mutations can be disregarded. In fact, GATA2 germline mutations can be considered the most common "initial hit" in pediatric MDS. In our experience, GATA2 deficiency accounts for 37% of primary pediatric MDS with monosomy 7. The prevalence of GATA2 mutations in MDS with monosomy 7 increases dramatically in adolescence where they are found in up to 72%. In comparison, 16% of pediatric patients with MDS and trisomy 8 have an underlying GATA2deficiency. The somatic mutational landscape in childhood MDS is associated with cytogenetic subgroups, i.e. SETBP1 and ASXL1 mutations are overrepresented in cases with monosomy 7. Interestingly, longitudinal NGS analysis and single colony sequencing indicate that SETBP1 lesions precede the development of ASXL1 mutations. We identified the genes SETBP1, ASXL1, NRAS, KRAS, RUNX1, PTPN11 and BCOR/ BCORL as the most frequent targets of recurrent mutations in a large cohort of pediatric patients with primary MDS. The biological significance of these genomic changes is currently not understood and warrants further studies. In contrast to pediatric MDS, signaling pathways involved in JMML have been better defined during recent years. Somatic aberrations in PTPN11, NRAS, KRAS, CBL, and NF1 genes lead to a constitutively overactive RAS pathway in leukemic cells. Additional activating mutations were identified in some JMML patients, including the RAS pathway gene RRAS, and concomitant mutations in SETBP1 and JAK3. The latter were postulated to develop as subclonal events during disease progression and to confer poor prognosis. However most recently, very rare clones with SETBP1 mutation were reported to be present at diagnosis in as much as 30% of JMML patients. This might indicate that multiple clones with different clonal composition arise during initial stages of disease, and therapy-driven selection pressure results in the expansion of these subclones. It is not clear how the somatic mutations interact with the epigenetic landscape in JMML clones, especially with regard to promoter hypermethylation, and what are the definitive biological consequences. In summary, a number of germline and somatic mutations have been identified which can initiate the development of abnormal hematopoiesis in children. Premalignant stem cells undergo evolutionary selection and produce somatically altered malignant clones resulting in myeloid transformation.

Disclosures
No relevant conflicts of interest to declare.