p53-/- synergizes with enhanced NrasG12D signaling to transform megakaryocyte-erythroid progenitors in acute myeloid leukemia.

Somatic mutations in TP53 and NRAS are associated with transformation of human chronic myeloid diseases to acute myeloid leukemia (AML). Here, we report that concurrent RAS pathway and TP53 mutations are identified in a subset of AML patients and confer an inferior overall survival. To further investigate the genetic interaction between p53 loss and endogenous NrasG12D/+ in AML, we generated conditional NrasG12D/+p53-/- mice. Consistent with the clinical data, recipient mice transplanted with NrasG12D/+p53-/- bone marrow cells rapidly develop a highly penetrant AML. We find that p53-/- cooperates with NrasG12D/+ to promote increased quiescence in megakaryocyte-erythroid progenitors (MEPs). NrasG12D/+p53-/- MEPs are transformed to self-renewing AML-initiating cells and are capable of inducing AML in serially transplanted recipients. RNA sequencing analysis revealed that transformed MEPs gain a partial hematopoietic stem cell signature and largely retain an MEP signature. Their distinct transcriptomes suggests a potential regulation by p53 loss. In addition, we show that during AML development, transformed MEPs acquire overexpression of oncogenic Nras, leading to hyperactivation of ERK1/2 signaling. Our results demonstrate that p53-/- synergizes with enhanced oncogenic Nras signaling to transform MEPs and drive AML development. This model may serve as a platform to test candidate therapeutics in this aggressive subset of AML.

Intracochlear pressure in response to high intensity, low frequency sounds in chinchilla.

Exposure to high intensity (blast) sounds can result in both conductive and sensorineural damage to hearing. This includes rupture of the tympanic membrane and dislocation of the middle ear ossicles, as well as damage to the inner and outer hair cells in the cochlea. A clearer understanding of how the hearing system responds to blast could help us better prevent auditory trauma, and support those who have been exposed to such sounds. Chinchillas are often used in studies of hearing due to the similarity between the chinchilla and human audiograms. The suitability of their use in research on auditory trauma from blast noise will depend on the extent to which cochlear pressures generated in chinchillas compare to those in humans. In order to gain a more detailed understanding of the response of the ear to high intensity sounds, a custom built sound concentrating horn was used to expose chinchilla cadaveric ears to a series of single frequency tones between 10 and 1280 Hz, with varying intensities from 90 to 194 dB SPL while intracochlear pressures were measured simultaneously in the scala vestibuli and scala tympani. These results were then compared to similar, previously published data from human cadavers. In both human and chinchillas, intracochlear pressures increased with applied sound pressure up to about 120 dB SPL, but began to saturate at higher intensities. The exact saturation point and the saturation pressures showed a strong frequency dependence. Intracochlear pressure magnitudes in chinchillas show some similarities with those measured in humans, but also significant differences, particularly at very high intensity levels such as those found in a blast. These differences should be taken into account when conducting blast studies in chinchillas.