How is Risk for Blood Cancers Inherited?


The Context: Scientists know that our risk for developing highly fatal blood cancers called ‘myeloid malignancies’ (such as acute myeloid leukemia) can be partially determined by mutations we inherit. However, which genes are involved, and how they influence disease risk has not been well understood.

The Study: The risk for certain blood cancers can be inherited due to mutations in a gene called CTR9, which is involved in blood stem cell production, finds a new study in Cell by NYSCF – Robertson Stem Cell Investigator Alumnus Vijay Sankaran, MD, PhD, of Boston Children’s Hospital.

The Importance: This study helps illuminate a major player in our risk of developing blood cancers (some of the most severe cancers), and could point to new opportunities for early detection and prevention or treatment.

Cancer is a disease of our DNA, with many complex contributors. As we age, our blood stem cells can accumulate mutations that increase our risk of developing blood cancers like acute myeloid leukemia. We can also be born with certain inherited mutations that could make us more likely to develop such diseases, but this piece of the puzzle is less explored. 

Dr. Sankaran’s team decided to look at genetic data from large groups of patients to see if they could identify mutations that might be influencing disease risk. Analysis across over 160,000 of individuals, many with myeloid malignancies, revealed a potential player: a mutation in a gene called CTR9. Those with this mutation, which causes the gene to be less effective, had a ten-fold increase in their risk of developing the disease.

Bad Blood

What is it about a mutation in CTR9 that makes one more likely to develop a blood disorder? 

The team found that this mutation in CTR9 caused an increase in blood stem cell production, by studying its effects on these cells in a dish and in mice. Blood stem cell production was increased because the CTR9 mutation altered transcription elongation, i.e., the way that RNA transcripts (made from our DNA) are elongated, which is a critical step in the expression and function of our genes.

Why does it matter if there’s an increase in blood stem cell production? 

Remember: the root of blood cancers lies with blood stem cells that carry mutations, and the more blood stem cells are in the body, the more chances there are that these cells will acquire mutations and then make more copies of themselves, in turn affecting the entire blood system. The initial mutation in CTR9 is making it more likely for these ‘bad seed’ cells to develop, multiply, and create excess blood, which leads to cancer.

Implications for Prevention

If scientists know the genes involved in heritable risk of blood cancers, then they can develop strategies for early screening, helping to identify those at risk and offer targeted prevention strategies. 

The team will continue exploring these possibilities and hope their work will help paint a clearer picture of heritability for these deadly disorders.

Journal Article:

Inherited blood cancer predisposition through altered transcription elongation
Jiawei Zhao, Liam D. Cato, Uma P. Arora, Erik L. Bao, Samuel C. Bryant, Nicholas Williams, Yuemeng Jia, Seth R. Goldman, Jyoti Nangalia, Michael A. Erb, Seychelle M. Vos, Scott A. Armstrong, Vijay G. Sankaran. Cell. 2024. DOI:

Diseases & Conditions:

Cancer and Blood

People mentioned: