Genomic And Epigenomic Profiling Of Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia is the most common malignancy in children and adolescents,and accounting for 20% of the acute leukemias of adults.Most of the ALLs originate from B precursor cells(B-ALL).Genomic sequence information has been lacking in adult B-ALL,whose outcome remains dismal,while a comparison between genomic abnormalities in adult and pediatric groups is useful to further decipher disease mechanisms.We used whole exome sequencing(WES),copy number variation(CNV)and molecular cytogenetics to catalog somatic mutations in 95 B-ALL patients(43 adults and 52 children).Targeted deep sequencing(TDS)was performed in a validation cohort of 179 adult and 199 pediatric B-ALLs.Eighty-four recurrent gene mutations were revealed by WES.Integrative analysis of the WES and copy number variation data identified the involvement of 9 functional categories of genes: key fusions(KFs),epigenetic modifiers(EMs),signaling molecules(SMs),transcription factors(TFs),tumor suppressors(TSs),actin binding/cytoskeletons(ABCs),ion binding proteins(IBPs),trans-membrane proteins(TPs)and the others.Mutually cooperative or exclusive relationships were revealed among some of these categories.Genomic landscapes suggested two distinct mechanisms involved in the leukemogenesis: one is mainly driven by KFs together with mutations of TFs and TSs;the other results from the abnormalities of TFs and TSs,in cooperation with mutations of EMs,SMs,ABCs and IBPs recapitulating the role of KFs.A panel of histone/DNA methylation modifiers(HMMs)were revealed to bear potential value of relatively favorable prognosis in both adult and childhood patients.We described the genome-wide abnormality patterns in adult B-ALL patients in comparison with those of pediatric cases,contributing to the understanding of leukemogenesis and the identification of potential new prognostic markers.