At the 2022 Annual Congress of the European Hematology Association, researchers from the Spanish National Cancer Institute (CINO) reported how high levels of the RNA-binding protein hnRNP-K could lead to bone marrow failure.

Pedro Aguilar-Garrido, a doctoral candidate in the CNIO's hematological malignancies clinical research unit, reported the findings in Saturday's presidential symposium.

In a poster presentation, Aguilar-Garrido and his colleagues also reported developing an inhibitor for hnRNP-K and validating its ability to slow the growth of leukemia cell lines.

hnRNP-K was first identified in 2015 by a team including Aguilar-Garrido's mentor Miguel Gallardo Delgado. It was originally identified as a tumor suppressor that played a role in the development of a subset of acute myeloid leukemia (AML) when one of its copies was not functional.

Subsequent studies showed that hnRNP-K's role in blood cancers was not limited to AML, but also played a role in other blood cancers, in particular B-cell lymphomas.

The researchers also showed in earlier work that depending on its context, hnRNP-K could function as either a tumor suppressor or an oncogene. This is likely because it can bind both single-stranded DNA, and interacts with kinases as well; hnRNP-K thus affects the regulation of multiple tumor suppressors and oncogenes depending on its specific binding partners.

In the work now presented at EHA, the group further extended the role of hnRNP-K to bone marrow failure. They also described the mechanism by which hnRNP-K overexpression led to cell senescence and, ultimately, bone marrow failure.

The team focused their work on nucleoli, the organelles within the nucleus where ribosomes translate RNA into proteins.

Here, higher levels of hnRNP-K resulted in higher overall levels of protein synthesis, which, over time, interfered with the proper function of those proteins and an inability of the proteasome to deal with them. This ultimately shortened the animals' lifespan "primarily due to dysplastic bone marrow and bone marrow failure," Aguilar-Garrido told the audience at the congress.

The team also found high levels of specific oncogenic proteins including mTOR and c-Myc, exemplifying that a protein can be overexpressed without itself being mutated.

Bone marrow failure can occur due to multiple reasons, and other studies presented at the conference delved into some of the causes of both inborn and acquired bone marrow failure.

A group from the IRCCS Istituto Gianna Gaslini reported on several patients with mutations in the CARD11 gene. CARD11 codes for a scaffolding protein that brings together its interaction partners in adaptive immunity, and like hnRNP-K, it can work via gain of function or loss of function depending on its exact mutation. The cases presented varied in both their symptoms and their response to medications, prompting the authors to conclude that their work "underlines the need for an enlarged molecular analysis in pediatric cases of MF and suggests that, in some patients, immune-mediated destruction of blood and marrow cells cooperate in generating the cytopenia."

Researchers at Prague's Charles University provided another example of such heterogeneity by comparing inborn aplastic anemia and hepatitis-associated bone marrow failure. The team found, in line with previous studies, that T-cell-mediated autoimmune reactions played a role in both cases. However, the pathogenic mechanisms appeared to differ.