Abstract
The pediatric T cell acute lymphoblastic leukemia (T-ALL) still remains a cancer with worst prognosis for high recurrence. Massive studies were conducted for the leukemia relapse based on diagnosis and relapse paired samples. However, the initially diagnostic samples may contain the relapse information and mechanism, which were rarely studied. In this study, we collected mRNA and microRNA (miRNA) data from initially diagnosed pediatric T-ALL samples with their relapse or remission status after treatment. Integrated differential co-expression and miRNA-transcription factor (TF)-gene regulatory network analyses were used to reveal the possible relapse mechanisms for pediatric T-ALL. We detected miR-1246/1248 and NOTCH2 served as key nodes in the relapse network, and they combined with TF WT1/SOX4/REL to form regulatory modules that influence the progress of T-ALL. A regulatory loop miR-429-MYCN-MFHAS1 was found potentially associated with the remission of T-ALL. Furthermore, we proved miR-1246/1248 combined with NOTCH2 could promote cell proliferation in the T-ALL cell line by experiments. Meanwhile, analysis based on the miRNA-drug relationships demonstrated that drugs 5-fluorouracil, ascorbate, and trastuzumab targeting miR-1246 could serve as potential supplements for the standard therapy. In conclusion, our findings revealed the potential molecular mechanisms of T-ALL relapse by the combination of co-expression and regulatory network, and they provide preliminary clues for precise treatment of T-ALL patients.
Highlights
T cell acute lymphoblastic leukemia (T-ALL), which accounts for 10%–15% of childhood and 25% of adult ALL cases,[1] is an aggressive hematologic neoplasm mainly caused by the malignant transformation of T-lymphocyte progenitors and the accumulation of genomic lesions in T cell development.[2]
We investigated potential molecular mechanisms for the relapse of pediatric T-ALL by integrating co-expression and miRNA-transcription factors (TFs)-gene network analysis
We validated miR-1246/1248-NOTCH2 could cooperate to promote cell proliferation in the Jurkat cell line, which may contribute to the relapse of pediatric T-ALL
Summary
T cell acute lymphoblastic leukemia (T-ALL), which accounts for 10%–15% of childhood and 25% of adult ALL cases,[1] is an aggressive hematologic neoplasm mainly caused by the malignant transformation of T-lymphocyte progenitors and the accumulation of genomic lesions in T cell development.[2] the therapeutic outcome of pediatric T-ALL has improved in recent decades (70%–75% long-term event-free survival rates),[3] it still remains a subgroup of cancers with the worst prognosis, and nearly 20% of child T-ALL patients still suffer relapse and cannot be salvaged by standard ther-. 184 Molecular Therapy: Nucleic Acids Vol 12 September 2018 a 2018 The Author(s). MAPK signaling pathway FoxO signaling pathway Central carbon metabolism in cancer Biosynthesis of antibiotics.
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