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.

Charles Mullighan, Stephen Hunger, Jinghui Zhang and colleagues report a genomic analysis of 264 pediatric and young adult T-lineage acute lymphoblastic leukemia (T-ALL) samples. They identify 106 candidate driver genes, 53 of which have not been described previously in pediatric T-ALL, as well as associations between mutations and disease stage or subtype. Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.

Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.

Medulloblastomas, a common type of malignant childhood brain tumour, are thought in the main to arise from the cerebellum, many of them involving aberrant signalling of a signalling pathway involving Sonic Hedgehog. There is substantial heterogeneity among medulloblastomas, however, and new work shows that a distinct subtype of medulloblastoma arises from the dorsal brainstem and is associated with altered Wnt signalling. Distinct molecular and clinical profiles of the subtypes have implications for future treatment. This suggests that subgroups of medulloblastoma are intrinsically different diseases, so therapeutic strategies may need to be tailored accordingly. Medulloblastomas are the most common malignant childhood brain tumours and are thought to arise from the cerebellum. There is substantial heterogeneity among medulloblastomas and some are thought to arise following aberrant Sonic Hedgehog pathway activation. It is now shown that a distinct subtype of medulloblastoma arises from the dorsal brainstem and is associated with altered WNT signalling. Distinct molecular and clinical profiles of the subtypes have implications for future treatment. Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour1,2,3,4. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype)3,4,5,6,7,8. The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype)1,3,4 arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.

Purpose: To conduct a pilot study to determine the safety, feasibility, and engraftment of haploidentical natural killer (NK) cell infusions after an immunosuppressive regimen in children with acute myeloid leukemia (AML). Patients and Methods: Ten patients (0.7 to 21 years old) who had completed chemotherapy and were in first complete remission of AML were enrolled on the Pilot Study of Haploidentical Natural Killer Cell Transplantation for Acute Myeloid Leukemia (NKAML) study. They received cyclophosphamide (60 mg/kg on day −7) and fludarabine (25 mg/m²/d on days −6 through −2), followed by killer immunoglobulin-like receptor–human leukocyte antigen (KIR-HLA) mismatched NK cells (median, 29 × 10⁶/kg NK cells) and six doses of interleukin-2 (1 million U/m²). NK cell chimerism, phenotyping, and functional assays were performed on days 2, 7, 14, 21, and 28 after transplantation. Results: All patients had transient engraftment for a median of 10 days (range, 2 to 189 days) and a significant expansion of KIR-mismatched NK cells (median, 5,800/mL of blood on day 14). Nonhematologic toxicity was limited, with no graft-versus-host disease. Median length of hospitalization was 2 days. With a median follow-up time of 964 days (range, 569 to 1,162 days), all patients remain in remission. The 2-year event-free survival estimate was 100% (95% CI, 63.1% to 100%). Conclusion: Low-dose immunosuppression followed by donor-recipient inhibitory KIR-HLA mismatched NK cells is well tolerated by patients and results in successful engraftment. We propose to further investigate the efficacy of KIR-mismatched NK cells in a phase II trial as consolidation therapy to decrease relapse without increasing mortality in children with AML.