Kinomics Profiling Of Pediatric Acute Myeloid Leukemia Based On Prognosis

Despite considerable progress has been made in elucidating the new diagnostic and prognostic markers over the past decades, acute myeloid leukemia (AML) remains a life threating malignancy in children. Previous studies defined AML patients into three prognostic groups (adverse, favorable and intermediate) based on cytogenetics. However, kinomics based signaling pathways have not been established based on these prognostic classes. This study addresses the kinomic profiling of these three prognostic groups to identify signaling pathways which could be novel druggable targets.

Primary blood and bone marrow samples of 93 pediatric AML patients (adverse 15%, favorable 20% and intermediate 65%) were included in this study. PepChip^TMKinomics microarray system was used to study the kinome profile of AML patients.

Pairwise comparisons among three prognostic groups on 992 target peptides from the kinome array reported 118 significantly different phosphorylated peptides (P<0.05). KEGG pathway enrichment analysis was performed for 118 proteins which corresponds to these significant 118 peptides following STRING database to assess whether the phenotypes of the prognosis groups could be distinguished based on the peptide phosphorylation profiles. The adverse group showed 54 significantly higher phosphorylated peptides compared to that of intermediate group and the pathway analysis revealed that those peptides were involved mostly in the following pathways such as T-cell receptor signaling, ErbB, B-cell receptor signaling, insulin signaling, focal adhesion (FAK), VEGF, JAK-STAT, cell cycles, MAPK and mTOR signaling pathways (top 10 pathways, based on the p-values for functional interactions of the proteins). Twenty four significantly phosphorylated target peptides were reported between adverse and favorable group, involved within the three pathways like VEGF, ErbB and insulin signaling pathways, but the p-values of these pathways based on interactions were less pronounced in comparison to the peptides of the previous pathways. The favorable group showed 12 significantly phosphorylated peptides compared to the intermediate group and only the ErbB pathway appeared from the pathway analysis. On the contrary, dephosphorylated peptides (19 in adverse vs. intermediate, 8 in adverse vs. favorable and 1 in favorable vs. intermediate group) did not exhibit any specific pattern to the signaling pathway. Likewise, logistic regression showed 7.14 times significantly higher mortality rate (P<0.005) in adverse group than that of intermediate group but not in the favorable group.

In conclusion, the adverse group attributed to higher mortality of the patients as expected and more target peptides were found in this group compared to the intermediate and even the favorable group. The kinomic profile approach determined different potential targets of pediatric AML patients based on their prognosis, hinting to different combinations of therapeutics.