It is expected to bring new ideas for early screening and intervention of leukemia.
Leukemia is a malignant tumor of the blood system, commonly known as "blood cancer".The occurrence of leukemia is related to many factors, including family genetic factors, chemical factors, physical factors, viral infections, etc.
Zhao Jiawei, a professor at Shenzhen Institute of Advanced Technology, and Vijay Sankaran, an associate professor at Boston Children's Hospital affiliated with Harvard Medical School, and a researcher at MIT's Broad Institute of Pharmacy, published the latest research in Cell.Using the UK Biobank, the team analyzed genetic data from more than 460,000 patient samples and identified a new risk factor for myeloid malignant blood tumors, which could provide new ideas for early screening and intervention.
"This work identifies a new gene, CTR9, that carries a genetic mutation that increases blood tumor susceptibility by a factor of 10, and we also define how this happens."These findings are important because we have discovered the regulatory mechanisms for this gene that could make blood tumor prevention possible."Vijay Sankaran, co-author of the paper, said.
Partial loss of CTR9 can effectively increase the number of artificial blood stem cells, but its basic biological function requires it to be present in cells to maintain cell function.
In the study, Zhao Jiawei, a professor at Shenzhen Institute of Advanced Medicine, Liam Cato, a postdoctoral fellow at Harvard Medical School, and Zhao Jiawei and Vijay Sankaran were co-authors.
The "young" cancer.
Unlike most other malignancies, leukemia is a "young" malignancy with a significantly lower average age of onset compared to other solid malignancies.According to the National Children's Cancer Surveillance Annual Report (2022), leukemia is still the first high-risk tumor in children.
Acute leukemia has the characteristics of acute onset, mortality rate, difficult to cure completely.With the unlimited accumulation and accumulation of leukemia cells in the bone marrow, it will gradually affect the normal bone marrow hematopoietic function, so that red blood cells, white blood cells, platelets, etc.
"At present, the cure for leukemia is highly dependent on healthy hematopoietic stem cell transplantation, and non-relative hematopoietic stem cell matching often takes a very long time, delaying effective treatment of patients."And Zacharias introduced it.
In this regard, the team proposed a hypothesis that some innate family heritable risk factors may play an important role in the mechanism of leukemia development."Although scientists have studied the occurrence of blood tumors such as leukemia and related pathogenesis in recent decades, there is still limited understanding of the role of genetic factors in blood tumors.And Zacharias said,
The development and improvement of high-throughput sequencing technology brings more possibilities for population genetics research.At the end of 2020, Zhao and his colleagues used the UK Biobank to analyze the genome-wide genetic information of more than 460,000 patients and find heritable risk factors that are highly family-related.
Decoding 460,000 samples to find new genetic pathogens
Finding new genetic pathogens for leukemia in more than 460,000 patient samples is not easy.The human genome contains more than 3 billion base pairs, nearly 30,000 genes, and finding gene mutants in the vast genome is more like a needle in a haystack.
"The entire research process can be divided into two important steps: finding and validating.One is to find the relevant gene mutant, and the other is to verify that the mutant causes leukemia.”
"The first thing we need to solve is the problem of statistical power, to verify that statistically such a large sample of statistics can be carried.After solving the statistical difficulties, the team conducted rare mutant-associated studies through genome-wide sequencing, eventually locking in CTR9 mutant, an important family risk factor for susceptibility to myeloid malignant blood tumors.
Hematopoietic stem cell amplification is the initial manifestation of leukemia, after excessive amplification, some hematopoietic stem cells may gradually lose their ability to self-regulate and differentiate into normal blood cells, and eventually become cancerous.Using human hematopoietic stem cells and immunodeficient mice as models, the team verified the effect of this risk factor on hematopoietic stem cells, and gradually solved the biological mechanism of leukemia.
In subsequent validation experiments over two years, the team found significant amplification of human long- and short-term hematopoietic stem cells if and only if CTR9 was partially missing, and that hematopoietic stem cells could not maintain long-term homeostasis.Notably, the gene mutant's leukaemia susceptibility increased tenfold compared to other, more common genetic factors.
In addition, fusion genes are the main indicators of leukemia diagnostic classification, prognosis stratification, targeted therapy and microresidual disease monitoring."There are many specific fusion genes that can cause leukemia, and the CTR9 gene mutation we found belongs to a gene that can affect the type of fusion gene that drives leukemia."And Zacharias said,
The work is highly advanced and the team used an impressive array of cutting-edge genomes, novel techniques for epigenome techniques and rigorous molecular biology analysis to analyze the role of this novel causative factor in human hematopoietic stem cell self-renewal." The reviewer commented on the outcome.
Exploring Leukemia Early Screening Strategies
For all diseases, prevention is more important than treatment, which is more critical in diseases such as malignant blood tumors.Raising the diagnostic level is undoubtedly at the heart of effective fighting cancer.
The study is groundbreaking to uncover a yet-to-be-reported familial gene that can significantly affect leukemia incidence, and through early screening of this risk factor, it is expected to advance targeted interventions for potential leukemia high-risk individuals.
Another reviewer noted in the review, "This is a very interesting study with a broad appeal to both clinical significance and molecular mechanisms.”
"Genetics is complex and unpredictable, and the effects of ethnic differences on certain diseases may be far greater than we thought.In the field of population genetics based on high-throughput sequencing technology, there is still a certain gap between China and developed countries.And Zacharias said,
Zhao Jiawei said that relying on foreign scientific research platforms to carry out better work, the future will further explore the steady state mechanism of hematopoietic stem cells and the mechanism of hematopoietic stem cells to leukemia.At the same time, exploring the establishment of China-specific population genetics database is more helpful to find suitable therapeutic targets for Chinese patients and explore the drug development path exclusively for Chinese.