Rzepa, E. | bioRxiv Science

bioRxiv2023

TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression

The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes in CEBPADM AML are GATA2 and TET2, however the molecular mechanisms underlying this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Elevated CEBPA levels, driven by CEBPANT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPADM AML induces a competitive advantage by increasing Gata2 promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.

cancer biology↗

bioRxiv2018

Dimensional Anhedonia and the Adolescent brain: Reward and Aversion Anticipation, Effort and Consummation.

Given the heterogeneity of depression the Research Domain Criteria Framework suggests a dimensional approach to understanding the nature of mental health and illness. Neural reward function has been suggested as underpinning the symptom of anhedonia in depression but less is known about how anhedonia is related to aversion processing. We examined how anhedonia relates to neural activity during reward and aversion processing in adolescents and emerging adults (N=84) in the age range 13-21yrs. Using a dimensional approach we examined how anhedonia and depression severity correlated with an fMRI task measuring anticipation, effort and consummation of reward and aversion. We show for the first time that the dimensional experience of anhedonia correlated with neural responses during effort to avoid aversion in the precuneus with a trend in the insula and during aversive consummation in the caudate. Using a categorical approach we also examined how the neural responses during each phase of the task differed in those with depression symptoms compared to healthy controls. We found participants with depression symptoms invested less physical effort to gain reward than controls and had blunted neural anticipation of reward and aversion in the precuneus, insula, and prefrontal cortex and blunted neural effort for reward in the putamen. This work highlights blunted neural responses to reward and aversion in depression and how anticipatory and consummatory anhedonia may be enhanced via dysfunctional neural processing of aversion. Future work will assess if these neural mechanisms can be used to predict blunted behavioural approach to reward and avoidance of negative experiences in adolescents at risk of depression.

neuroscience↗