Early T-cell precursor acute lymphoblastic leukaemia (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 leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole genome and exome sequencing of 40 cases, identified two subtypes that differ in severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and the lymphoid transcription factor IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL with 32–39 chromosomes are characterized by TP53 alterations (91.2%) which are commonly present in non-tumor cells, and alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras- and PI3K signaling pathways, and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.

Relapsed acute lymphoblastic leukaemia (ALL) is a leading cause of death due to disease in young people, but the biologic determinants of treatment failure remain poorly understood. Recent genome-wide profiling of structural DNA alterations in ALL have identified multiple submicroscopic somatic mutations targeting key cellular pathways 1, 2, and have demonstrated substantial evolution in genetic alterations from diagnosis to relapse3. However, detailed analysis of sequence mutations in ALL has not been performed. To identify novel mutations in relapsed ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosisrelapse cases and 270 acute leukaemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase (HAT) CREB-binding protein (CBP) 4 . The mutations were either present NIH Public Access Author ManuscriptNature. Author manuscript; available in PMC 2011 September 10. at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the HAT domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. These results extend the landscape of genetic alterations in leukaemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL.Acute lymphoblastic leukaemia (ALL) is the commonest childhood malignancy 5 , and is a leading cause of cancer-related death in young people. Several structural chromosomal alterations in ALL, including rearrangement of MLL and the Philadelphia chromosome 6 are associated with a high risk of treatment failure and relapse. However, many ALL cases that fail therapy lack these alterations, and the biologic basis of treatment failure in these cases is poorly understood. Genome-wide profiling of ALL has identified multiple recurring submicroscopic genetic alterations targeting lymphoid development, cell cycle regulation, tumour suppression and apoptosis 1,2 , and has identified genetic alterations that predict a high risk of relapse, including deletion of IKZF1 (IKAROS) 7, 8. Moreover, profiling of structural DNA alterations in matched diagnosis and relapse samples has demonstrated that in the majority of cases there are substant...

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R) and 20 older children (MLL-R cases) with leukemia. Our data demonstrated infant MLL-R ALL to have one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite the paucity of mutations, activating mutations in kinase/PI3K/RAS signaling pathways were detected in 47%. Surprisingly, however, these mutations were often sub-clonal and frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (a mean of 6.5/case versus 1.3/case, P=7.15×10−5) and contained frequent mutations (45%) in epigenetic regulators, a category of genes that with the exception of MLL was rarely mutated in infant MLL-R ALL.

T cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy with dismal overall prognosis, exhibiting up to a 25% relapse rate, mainly due to the absence of non-cytotoxic targeted therapy options. Despite the fact that drugs targeting the function of key epigenetic factors have been approved in the context of hematopoietic disorders1 and the recent identification of mutations affecting chromatin modulators in a variety of leukemias2,3, “epigenetic” drugs are not currently used for TALL treatment. Recently, we described a tumor suppressor role of the polycomb repressive complex 2 (PRC2) in this tumor4. Here we sought out to delineate the role of histone 3 lysine 27 (H3K27) demethylases, JMJD3 and UTX. We show that JMJD3 is essential for initiation and maintenance of disease, as it controls important oncogenic gene targets through the modulation of H3K27 methylation. In contrast, UTX acts a tumor suppressor and frequently genetically inactivated in T-ALL. Moreover, we demonstrate that the small molecule inhibitor GSKJ45 affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with similar enzymatic function can play opposing roles in the context of the same disease and pave the way for the use of a new category of epigenetic inhibitors in hematopoietic malignancies.