Whole-exome sequencing and microRNA profiling reveal PI3K/AKT pathway’s involvement in juvenile myelomonocytic leukemia

Abstract

Background: Clinical studies and genetic analyses have revealed that juvenile myelomonocytic leukemia (JMML) is caused by somatic and/or germline mutations of genes involved in the RAS/MAPK signalling pathway. Given the vastly different clinical prognosis among individual patients that have had this disease, mutations in genes of other pathways may be involved.

Methods: In this study, we conducted whole-exome and cancer-panel sequencing analyses on a bone marrow sample from a 2-year old juvenile myelomonocytic leukemia patient. We also measured the microRNA profile of the same patient’s bone marrow sample and the results were compared with the normal mature monocytic cells from the pooled peripheral blood.

Results: We identified additional novel mutations in the PI3K/AKT pathway and verified with a cancer panel targeted sequencing. We have confirmed the previously tested PTPN11 gene mutation (exon 3 181G>T) in the same sample and identified new nonsynonymous mutations in NTRK1, HMGA2, MLH3, MYH9 and AKT1 genes. Many of the microRNAs found to be differentially expressed are known to act as oncogenic MicroRNAs (onco-MicroRNAs or oncomiRs), whose target genes are enriched in the PI3K/AKT signalling pathway.

Conclusions: Our study suggests an alternative mechanism for JMML pathogenesis in addition to RAS/MAPK pathway. This discovery may provide new genetic markers for diagnosis and new therapeutic targets for JMML patients in the future.

Graphical abstract

Keywords

single-cell / RNA-Seq / differential expression

References

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SUPPLEMENTARY MATERIALS

The supplementary materials can be found online with this article at 10.1007/s40484-017-0125-2.

ACKNOWLEDGEMENTS

This work was partially supported by the Mizzou Advantage Program at the University of Missouri and National Institute of Health (R01-GM100701). The authors would like to thank the Informatics Core of the University of Missouri for providing the computing resources of this work. The authors would also like to thank Mr. Miqdad O. Dhariwala for providing access to and help with Canvas image manipulation software.

COMPLIANCE WITH ETHICS GUIDELINES

The authors Saad M Khan, Jason E Denney, Michael X Wang and Dong Xu declare they that have no conflict of interests.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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