Jacobsson, S. | Search bioRxiv

bioRxiv2023

Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between breakpoint partners (MNX1 and ETV6) has only been reported in a subset of cases. However, a universal feature is the strong transcript and protein expression of MNX1, a homeobox transcription factor that is normally not expressed in hematopoietic cells. Here, we map the translocation breakpoints on chromosomes 7 and 12 in affected patients to a region proximal to MNX1 and either introns 1 or 2 of ETV6. The frequency of MNX1 overexpression in pediatric AML (n=1556, own and published data) is 2.4% and occurs predominantly in t(7;12)(q36;p13) AML. Chromatin interaction assays in a t(7;12)(q36;p13) iPSC cell line model unravel an enhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Our data suggest that enhancer-hijacking is a more common and overlooked mechanism for structural rearrangement-mediated gene activation in AML. Key pointsO_LIExpression analysis of over 1500 pediatric AML samples demonstrates MNX1 expression as a universal feature of t(7;12)(q36;p13) AML as well as in rare cases without t(7;12)(q36;p13) C_LIO_LIMNX1 is activated by an enhancer-hijacking event in t(7;12)(q36;p13) AML and not, as previously postulated, by the creation of a MNX1::ETV6 oncofusion gene. C_LI

cancer biology↗

bioRxiv2019

A regulatory RNA is associated to invasive meningococcal disease in Europe

The strictly human pathogen Neisseria meningitidis is a commensal bacterium but can occasionally turn lethal causing septicaemia and meningitis. The mechanisms of how the meningococcus shifts to invasive infection remain poorly understood. Here we demonstrate that an eight base-pair tandem repeat deletion in the 5-untranslated region of the polysaccharide capsular biosynthesis operon results in a hypercapsulation phenotype in clinical isolates. The increased capsule production significantly improves the bacterium survival in human serum while impairing its ability to adhere and colonise human pharyngeal cells. Among 4501 reported meningococcal cases in Europe from 2010-2018, the loss of an eight base-pair tandem repeat is three times more prevalent in invasive isolates (16.3%) compared to carrier isolates (5.1%).Combined results indicate that polymorphisms in this regulatory RNA contributes to meningococcal virulence.\n\nImportanceIn this study we report a regulatory RNA to be directly involved in clinical manifestation of meningococcal disease. Using readily accessible WGS of meningococcus, we have now demonstrated that regulatory RNAs directly contribute to the progression of invasive meningococcal infection. We believe this novel combination of molecular and comparative regulatory RNA study could be used for the identification of additional RNAs involved in not only meningococcus but also pave the way for similar studies in other important bacterial pathogens. The identification of specific regulatory RNAs will no doubt facilitate clinicians, microbiologists, and public health practitioners to adjust their diagnostic techniques and treatments to best fit the condition of the patients.

microbiology↗