Transcriptome Analysis of Monozygotic Twin Brothers with Childhood Primary Myelofibrosis

Abstract

Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder in human bone marrow. Over 50% of patients with myelofibrosis have mutations in JAK2, MPL, or CALR. However, these mutations are rarely detected in children, suggesting a difference in the pathogenesis of childhood PMF. In this study, we investigated the response to drug treatment of a monozygotic twin pair with typical childhood PMF. The twin exhibited different clinical outcomes despite following the same treatment regimen. The transcriptomic profiles of patient samples after drug treatment (E2 and Y2) were significantly different between the twin pair, which is consistent with the observation that the drug treatment was effective only in the younger brother, despite the twin being genetically identical. Bioinformatics analysis of the drug-responsive genes showed that the JAK-STAT pathway was activated in the cured younger brother, which is opposite to the pathway inhibition observed in adult PMF cases following treatment. Moreover, apoptosis and cell cycle processes were both significantly influenced by drug treatment in the sample of younger brother (Y2), implying their potential association with the pathogenesis of childhood PMF. Gene mutations in JAK2, MPL, or CALR were not observed; however, mutations in genes including SRSF2 and SF3B1 occurred in this twin pair with childhood PMF. Gene fusion events were extensively screened in the twin pair samples and the occurrence of IGLV2-14-IGLL5 gene fusion was confirmed. The current study reported at transcriptomic level the different responses of monozygotic twin brothers with childhood PMF to the same androgen/prednisone treatment regimen providing new insights into the potential pathogenesis of childhood PMF for further research and clinical applications.

Pervasive Inter-Individual Variation in Allele-Specific Expression in Monozygotic Twins

“…What mechanisms might explain the observed ASE discordance in MZ co-twins? Data from prior RNA-Seq studies in co-twins (Baranzini et al, 2010; Lin et al, 2012a; Brown et al, 2014; Hibaoui et al, 2014; Buil et al, 2015; Dixon et al, 2015; Ding et al, 2017; Santoni et al, 2017) indicate that the differential allele expression of autosomal genes best reflects dynamic regulation processes consistent with either an allele being preferentially silenced or an inactive allele being restored. The biallelic expression of genes is a regulatory mechanism that outbalances the harmful effects of pathogenic expression-altering or loss-of-function risk variant alleles (Adzhubei et al, 2010; Landrum et al, 2016; Vaser et al, 2016).…”

Definition, Epidemiology, Pathophysiology, and Essential Criteria for Diagnosis of Pediatric Chronic Myeloid Leukemia

“…However, concerning the typical mutations a lower incidence of mutation JAK2-V617F has been reported in childhood ET and PV, and fewer CALR mutations were found in children with ET [ 34 ]. Primary (osteo)myelofibrosis (PMF) also termed idiopathic myelofibrosis (IMF) is extremely rare in children [ 35 ], although sporadic childhood cases with PMF/IMF have been described [ 36 ]. Compared to adults, phenotypic differences appear to exist in children with PMF/IMF which are typically also found in pediatric CML, such as a frequent presence of marrow eosinophilia, only a low degree of marrow collagen fibrosis, the absence of significant osteosclerosis and megakaryocytic dysplasia with hypolobulated megakaryocytes with hyperchromatic nuclei and micromegakaryocytes.…”