The Genomic Complexity of Early T-Cell Progenitor Acute Lymphoblastic Leukemia

Early T-cell precursor acute lymphoblastic leukemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signaling, inactivating lesions disrupting hematopoietic development, and histone-modifying genes. We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumors, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukemia hematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.