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.
Highlights
Primary myelofibrosis (PMF) is an agnogenic myeloid metaplasia resulting from abnormal clonal myeloid stem cells in the bone marrow (BM) [1,2,3]
While investigating the key genes involved in childhood PMF, we found that 20 genes, including JAK2, were involved in all of the Gene Ontology (GO) functions enriched in the drug-responsive set (Figure 5C)
Our results suggest the involvement of different pathogenic mechanisms in childhood PMF, and imply that the JAK gene family is involved in this disease in a manner that is independent of the documented JAK2-V617F mutation
Summary
Primary myelofibrosis (PMF) is an agnogenic myeloid metaplasia resulting from abnormal clonal myeloid stem cells in the bone marrow (BM) [1,2,3]. PMF is characterized by BM diffuse fibrosis, splenomegaly, and extramedullary hematopoiesis, while the fibrous tissue produces few red blood cells (RBCs), leading to a failure of hematopoiesis [1,2,3]. PMF is frequently observed prior to the onset of other diseases such as acute myeloid leukemia (AML) [4,5]. Effective approaches for the treatment of this disease include allogeneic hematopoietic stem cell transplantation (HSCT) [6] and splenectomy [7]. The incidence of PMF is approximately 1 case per 100,000 people, with a median age of onset of 60 years [8]. Most studies have focused more on the clinical and cytogenetic phenotypes associated with the disease, rather than on drug therapies and related mechanisms
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