Failure of human rhombic lip differentiation underlies medulloblastoma formation

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB

Integrated airborne investigation of the air composition over the Russian sector of the Arctic

International audienceThe change of the global climate is most pronounced in the Arctic, where the air temperature increases 2 to 3 times faster than the global average. This process is associated with an increase in the concentration of greenhouse gases in the atmosphere. There are publications predicting the sharp increase in methane emissions into the atmosphere due to permafrost thawing. Therefore, it is important to study how the air composition in the Arctic changes in the changing climate. In the Russian sector of the Arctic, the air composition was measured only in the surface atmospheric layer at the coastal stations or earlier at the drifting stations. Vertical distributions of gas constituents of the atmosphere and aerosol were determined only in a few small regions. That is why the integrated experiment was carried out to measure the composition of the troposphere in the entire Russian sector of the Arctic from on board the Optik Tu-134 aircraft laboratory in the period of ​​​​​​​4 to 17 September of 2020. The aircraft laboratory was equipped with contact and remote measurement facilities. The contact facilities were capable of measuring the concentrations of CO2, CH4, O3, CO, NOx​​​​​​​, and SO2, as well as the disperse composition of particles in the size range from 3 nm to 32 µm, black carbon, and organic and inorganic components of atmospheric aerosol. The remote facilities were operated to measure the water transparency in the upper layer of the ocean, the chlorophyll content in water, and spectral characteristics of the underlying surface. The measured data have shown that the ocean continues absorbing CO2. This process is most intense over the Barents and Kara seas. The recorded methane concentration was increased over all the Arctic seas, reaching 2090 ppb in the near-water layer over the Kara Sea. The contents of other gas components and black carbon were close to the background level.In bioaerosol, bacteria predominated among the identified microorganisms. In most samples, they were represented by coccal forms, less often spore-forming and non-spore-bearing rod-shaped bacteria. No dependence of the representation of various bacterial genera on the height and the sampling site was revealed. The most turbid during the experiment was the upper layer of the Chukchi and Bering seas. The Barents Sea turned out to be the most transparent. The differences in extinction varied by more than a factor of 1.5. In all measurements, except for the Barents Sea, the tendency of an increase in chlorophyll fluorescence in more transparent waters was observed

Integrated airborne investigation of the air composition over the Russian Sector of the Arctic

International audienceThe change of the global climate is most pronounced in the Arctic, where the air temperature increases two to three times faster than the global average. This process is associated with an increase in the concentration of greenhouse gases in the atmosphere. There are publications predicting the sharp increase of methane emissions into the atmosphere due to permafrost thawing. Therefore, it is important to study how the air composition in the Arctic changes in the changing climate. In the Russian sector of the Arctic, the air composition was measured only in the surface atmospheric layer at the coastal stations or earlier at the drifting stations. Vertical distributions of gas constituents of the atmosphere and aerosol were determined only in few small regions. That is why the integrated experiment was carried out to measure the composition of the troposphere in the entire Russian sector of the Arctic from onboard the Optik Tu-134 aircraft laboratory in the period of September 4 to 17 of 2020. The aircraft laboratory was equipped with contact and remote measurement facilities. The contact facilities were capable of measuring the concentrations of CO2, CH4, O3, CO, NOX, and SO2, as well as the disperse composition of particles in the size range from 3 nm to 32 µm, black carbon, organic and inorganic components of atmospheric aerosol. The remote facilities were operated to measure the water transparency in the upper layer of the ocean, the chlorophyll content in water, and spectral characteristics of the underlying surface. The measured data have shown that the ocean continues absorbing СО2. This process is most intense over the Barents and Kara Seas. The recorded methan

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB