A common characteristic of malignant cells derived from patients with Hodgkin's disease (HD) is a high level of constitutive nuclear NF-kB/Rel activity, which stimulates proliferation and confers resistance to apoptosis. We have analysed the mechanisms that account for NF-kB activation in a panel of Hodgkin/Reed-Sternberg (H-RS) cell lines. Whereas two cell lines (L428 and KMH-2) expressed inactive IkBa, no signi®cant changes in NF-kB or IkB expression were seen in other H-RS cells (L591, L1236 and HDLM-2). Constitutive NF-kB was susceptible to inhibition by recombinant IkBa, suggesting that neither mutations in the NF-kB genes nor posttranslational modi®cations of NF-kB were involved. Endogenous IkBa was bound to p65 and displayed a very short half-life. IkBa degradation could be blocked by inhibitors of the NF-kB activating pathway. Proteasomal inhibition caused an accumulation of phosphorylated IkBa and a reduction of NF-kB activity in HDLM-2 and L1236 cells. By in vitro kinase assays we demonstrate constitutive IkB kinase (IKK) activity in H-RS cells, indicating ongoing signal transduction. Furthermore, H-RS cells secrete one or more factor(s) that were able to trigger NF-kB activation. We conclude that aberrant activation of IKK's, and in some cases defective IkBs, lead to constitutive nuclear NF-kB activity, which in turn results in a growth advantage of Hodgkin's disease tumor cells.

Infant high grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histological review, methylation profiling, custom panel and genome/exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an 'intrinsic' spectrum of disease specific to the infant population. These included those with targetable MAP-kinase alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n=31), NTRK1/2/3 (n=21), ROS1 (n=9) and MET (n=4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly supports the concept that infant gliomas require a change in diagnostic practice and management.

Rhabdoid tumors of early infancy are highly aggressive with consequent poor prognosis. Most cases show inactivation of the SMARCB1 (also known as INI1 and hSNF5) tumor suppressor, a core member of the ATP-dependent SWI/SNF chromatin-remodeling complex. Familial cases, described as rhabdoid tumor predisposition syndrome (RTPS), have been linked to heterozygous SMARCB1 germline mutations. We identified inactivation of another member of the SWI/SNF chromatin-remodeling complex, its ATPase subunit SMARCA4 (also known as BRG1), due to a SMARCA4/BRG1 germline mutation and loss of heterozygosity by uniparental disomy in the tumor cells of two sisters with rhabdoid tumors lacking SMARCB1 mutations. SMARCA4 is thus a second member of the SWI/SNF complex involved in cancer predisposition. Its general involvement in other tumor entities remains to be established.