EHA 2022: Dysregulation of RNA binding proteins drive hematopoietic stem cell exhaustion and bone marrow failure

11 Jun 2022
EHA 2022: Dysregulation of RNA binding proteins drive hematopoietic stem cell exhaustion and bone marrow failure

Translation of mRNA is an intricate process involving crosstalk between nucleoli and ribosomes.

Dysregulation or impairment of this process can result in nucleolus stress, which plays an important role in disease pathologies including cancer.

Furthermore, abnormalities in the function and structure of ribosomal components may lead to diseases such as bone marrow failure.

One such component is hnRNP K, which is an RNA binding protein that processes pre-mRNA in the nucleoli into mature mRNA ready for translation by ribosomes.

In this study, we aimed to elucidate how dysregulation of hnRNP K impacts haematopoietic stem cell biology.

Hnrnpk was overexpressed in mouse embryonic fibroblasts, which were subsequently exposed to actinomycin D to trigger nucleolus stress.

The hallmarks of nucleolus stress were assessed using confocal microscopy and flow cytometry and qRT-PCR were used to investigate the underlying molecular mechanisms.

The impact of Hnrnpk overexpression was also evaluated in an inducible tamoxifen mouse model (HnrnpkTg-Ubc-creERT2) by analysing the survival and phenotype of the mice.

We discovered that overexpression of Hnrnpk resulted in elevated gene and protein expression of Ncl, mTor, and c-Myc as well as an increase in global protein synthesis and inversely correlated with proteasome function.

Furthermore, cells that overexpressed Hnrnpk showed hallmarks of nucleolus stress such as an increased number of nucleoli and enlarged total area of the nucleoli and nucleus and were more likely to display a senescent cell phenotype.

The induction of nucleolus stress by actinomycin D promoted the expression of hnRNP K in these cells.

Mice with inducible overexpression of Hnrnpk exhibited a reduction in lifespan, primarily due to dysplastic bone marrow and bone marrow failure.

Further analyses revealed a strong reduction of CD34 and B cells, leukopenia, anaemia, and thrombocytopenia.

Taken together, these data indicate that hnRNP K overexpression in cells prompts an increase in nucleoli activity through ribosome biogenesis and higher global translation followed by cell senescence.

This dysregulation results in bone marrow failure and exhaustion of haematopoietic stem cells in an in vivo mouse model.

Source: EHA