Discovery of novel recurrent mutations and rearrangements in early T-cell precursor acute lymphoblastic leukemia by whole genome sequencing

Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole genome sequencing of tumour and normal DNA from 12 children with ETP ALL and assessed the frequency of somatic alterations in 52 ETP and 42 non-ETP T-ALL samples by sequencing and DNA copy number analysis. ETP ALL was characterised by a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF); alterations disrupting haemopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1, EP300); and inactivating mutations in histone modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of mutation including DNM2, ECT2L and RELN. Ten of 12 ETP ALL cases harboured chromosomal rearrangements, several of which complex and resulted in the expression of novel chimeric in-frame fusion genes disrupting haemopoietic regulators. Thus, similar to myeloid malignancies, mutations that drive proliferation, impair differentiation and disrupt histone modification are hallmarks of ETP ALL. Moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haemopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

52

Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen SC, Wei L, Collins-Underwood JR, Ma J, Roberts KG, Pounds SB, Ulyanov A, Becksfort J, Gupta P, Huether R, Kriwacki RW, Parker M, McGoldrick DJ, Zhao D, Alford D, Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Basso G, Hunger SP, Loh ML, Devidas M, Wood B, Winter S, Dunsmore KP, Fulton RS, Fulton LL, Hong X, Harris CC, Dooling DJ, Ochoa K, Johnson KJ, Obenauer JC, Evans WE, Pui CH, Naeve CW, Ley TJ, Mardis ER, Wilson RK, Downing JR, Mullighan CG