Results and Discussion:
Samples from 14 cases diagnosed to have JMML between 1979 and December 2019 were available for testing; all patients were under age 13; 3 of these cases were included in previous publications.13, 14 Four of the 12 archived samples showed increased necrosis on flow cytometry and therefore were excluded from the analysis. Figure 1 shows CD14/CD16 monocyte profiling on the remaining 10 JMML samples (8 archival samples; 2 fresh samples) along with the associated JMML mutation.
In four patients (Panel A), MO1 monocytes (CD14++/CD16) were >95% of total monocytes (range 95.1 to 98.8%). Three of these had somatic PTPN11 mutations (PTPN11 p.A72V,PTPN11 p.E76A, PTPN11 p.A72T), while one case had a novelCBL p.L62F mutation. No such increase in MO1 population was observed in any of the four Monosomy-7 patients (despite having concurrent PTPN11 or KRAS mutations) or the two Noonan syndrome cases with PTPN11 p.E73I mutation (Panel B). This distinct clustering of JMML cases based on monocyte subsets was unexpected. Molecular studies have identified clinically significant clustering of JMML cases with somatic PTPN11 mutations associated with poorer prognosis than those with germline mutations as seen in Noonan syndrome. Epigenetic studies have also reported increased global 5-methylcytosine in JMML associated with somatic PTPN11 mutations as compared to the Noonan syndrome cases.15, 16
In summary, this pilot study is the first to evaluate monocyte subsets in JMML and correlate with underlying JMML genetics. Flow-based monocyte profiling of JMML patients is not diagnostic of JMML per se but the presence of >95% classical monocytes identifies a subset of cases with underlying deleterious somatic PTPN11 mutations. In adult CMML, the monocyte subset repartitioning showed normalization in patients who responded to hypomethylating agents (HMA).3 Thus, monocyte profiling may be a useful tool in characterizing the abnormal monocyte proliferation in JMML and for therapeutic monitoring.
Conflict of interest:The authors have no conflicts of interest