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Single target for pre-malignant bone marrow cancers?

Mechanisms that create healthy red blood cells can also start myelodysplasia (MDS) syndromes. MDS are pre-malignant blood disorders. In each, bone marrow stops producing an adequate number of healthy blood cells. Knowing the how and why of blood cell formation may possibly help interrupt these disorders.


MDS, or myelodysplasia syndromes are a group of cancers in which immature blood cells in the bone marrow do not mature to become healthy blood cells. MDS can lead to acute myeloid leukemia (AML), a fast-spreading blood cancer that can be deadly if not treated immediately.

The work appears in Nature Immunology, published online Dec. 26, 2016.

Research led by cancer biologist Daniel Starczynowski PhD, department of Cancer Biology at Cincinnati Children's Hospital Medical Center, found over production of one particular protein —TRAF6  — in hematopoietic (blood) cells initiates MDS.


TRAF6 normally functions as an immune sensor rooting out pathogens in our blood. However:

"We found TRAF6 over expression in mouse hematopoietic stem cells results in impaired blood cell formation leading to bone marrow failure.

"Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and related proteins responsible for MDS."

Daniel Starczynowski PhD, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.


Testing on mice as models for human MDS/AML, Starczynowski's researchers identified a new form of TRAF6 called  hnRNPA1, which binds RNA proteins into a new structure. They also found molecular interactions with the protein Cdc42, which is involved in regulation of the cell cycle to bring about cell division and can thus promote cancers. These interactions could be a potential treatment targets for MDS.

Starczynowski intends in the future to test these targets in mice MDS models for possible human therapies. Researchers were only able to identify these molecular targets by conducting a global analysis of human leukemia cells, which allowed them to the see the entire complement of proteins regulated by TRAF6.


Beyond the potential for new therapeutic approaches to treat MDS or AML, the study reveals a critical immune-related function for TRAF6.

In addition to its response to various pathogens, TRAF6 regulates the conversion of single-stranded ribonucleic acid (RNA) into various mature RNA products such as mRNAs, tRNAs, and rRNAs all on their way to becoming proteins. Technically, the process is called RNA isoform expression.


TRAF6's regulate RNA isoform expression which is critical to the function of blood cells. But it may also be revealing another way cells respond to infection.

A single gene has the ability to produce multiple proteins, each different in structure and made up of unique components — a process regulated by splicing only mature RNA (mRNA) — which can then continue to diversify its protein output and create even more new proteins.

This process creates diversity in what is called the proteome, or the entire set of proteins made by all the genes in our body. The flexibility of this conversion of RNA into mRNA promotes cell energy. But, it may also be a response to attacks from pathenogens. Increasing the diversification of proteins may be allowing the body to create new antitoxin defenses.

Abstract
Toll-like receptor (TLR) activation contributes to premalignant hematologic conditions, such as myelodysplastic syndromes (MDS). TRAF6, a TLR effector with ubiquitin (Ub) ligase activity, is overexpressed in MDS hematopoietic stem/progenitor cells (HSPCs). We found that TRAF6 overexpression in mouse HSPC results in impaired hematopoiesis and bone marrow failure. Using a global Ub screen, we identified hnRNPA1, an RNA-binding protein and auxiliary splicing factor, as a substrate of TRAF6. TRAF6 ubiquitination of hnRNPA1 regulated alternative splicing of Arhgap1, which resulted in activation of the GTP-binding Rho family protein Cdc42 and accounted for hematopoietic defects in TRAF6-expressing HSPCs. These results implicate Ub signaling in coordinating RNA processing by TLR pathways during an immune response and in premalignant hematologic diseases, such as MDS.

Contributing authors: Jing Fang, Lyndsey C Bolanos, Kwangmin Choi, Xiaona Liu, Susanne Christie, Shailaja Akunuru, Rupali Kumar, Dehua Wang, Xiaoting Chen, Kenneth D Greis, Peter Stoilov, Marie-Dominique Filippi, Jaroslaw P Maciejewski, Guillermo Garcia-Manero, Matthew T Weirauch, Nathan Salamonis, Hartmut Geiger, Yi Zheng & Daniel T Starczynowski

Key search terms: Leukaemia Toll-like receptors

Funding support for the study came in part from work Cincinnati Children's Hospital Research Foundation, the American Society of Hematology, the National Institute of Health (RO1HL111103, RO1DK102759, RO1HL114582), Gabrielle's Angel Foundation for Cancer Research, Edward P. Evans Foundation, and Leukemia Lymphoma Society.

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Healthy red blood cells
Image Credit: public domain

 


 


Phospholid by Wikipedia