Quantitative Biology

, Volume 6, Issue 1, pp 85–97 | Cite as

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

  • Saad M. Khan
  • Jason E. Denney
  • Michael X. Wang
  • Dong Xu
Research Article



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.


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.


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.


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.


single-cell RNA-Seq differential expression 



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.

Supplementary material

40484_2017_125_MOESM1_ESM.pdf (852 kb)
Supplementary material, approximately 851 KB.
40484_2017_125_MOESM2_ESM.xls (48 kb)
Supplementary Table S1: List of upregulated microRNAs with log2Foldchange > 2 are shown along with their p-values and adjusted p-values. Since the comparison of one JMML patient was done against 10 replicates of Adult monocytic cells (shown as SRR ids) the read counts of each of the Samples and replicates is also shown. The onco-miRs are shown in red. The onco-miRs present in the network (in Supp. Fig S5) are shown in bold red.
40484_2017_125_MOESM3_ESM.xls (46 kb)
Supplementary Table S2: List of downregulated microRNAs with log2Foldchange < −2 are shown along with their p-values and adjusted p-values. Since the comparison of one JMML patient was done against 10 replicates of Adult monocytic cells (shown as SRR ids) the read counts of each of the Samples and replicates is also shown. The onco-miRs are shown in red.
40484_2017_125_MOESM4_ESM.xls (118 kb)
Supplementary Table S3: All microRNAs which were obtained from sRNAbench and had a significanct read count. The results below show edgeR results for comparison of one bonemarrow sample against 10 adult monocytic cell replicates.
40484_2017_125_MOESM5_ESM.xls (35 kb)
Supplementary Table S4: Selected microRNAs as shown in Figure 3 and their enrichment p-values with respect to each pathway obtained from miRPath (Vlachos, I. S. et al. 2015) are shown. All these microRNAs below were differntially expressed and had significant p-values from edgeR results (Supp Table S3).
40484_2017_125_MOESM6_ESM.cys (5 mb)
Supplementary material, approximately 4.97 MB.


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Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Informatics Institute and C. S. Bond Life Sciences CenterUniversity of MissouriColumbiaUSA
  2. 2.Department of Pathology and Anatomical SciencesUniversity of MissouriColumbiaUSA
  3. 3.Department of Computer ScienceUniversity of MissouriColumbiaUSA

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