By Diaowen Hui, Reporter, China Science DailyLeukemia, also known as "blood cancer," is a malignant tumor of the blood system. The onset of leukemia is related to various factors, including genetic factors, chemical factors, physical factors, and viral infections. Exploring the pathogenesis of leukemia helps to bring new strategies for early screening and intervention of leukemia.Professor Zhao Jiawei from the School of Pharmacy of Shenzhen University (Provisional) and Researcher at the Shenzhen Advanced Technology Research Institute of the Chinese Academy of Sciences, collaborated with Vijay Sankaran, an Associate Professor at the Harvard Medical School and a Researcher at the Broad Institute of MIT and Harvard affiliated with the Boston Children's Hospital, to analyze over 460,000 patient samples using genetic analysis from the UK Biobank. They discovered a new pathogenic risk factor for myeloid malignancies, which could provide new insights for potential early screening and intervention of leukemia. The research findings were published in the journal Cell."This work identifies a new gene - CTR9. The gene carries a genetic mutation that increases susceptibility to hematologic malignancies by tenfold, and we have defined how this occurs. These findings are significant because we have discovered the regulatory mechanisms of this gene, making it possible to prevent hematologic malignancies," said Vijay Sankaran, co-corresponding author of the paper.
Acute leukemia is characterized by its rapid onset, high mortality rate, and difficulty in complete cure. As leukemia cells proliferate and accumulate uncontrollably in the bone marrow, the normal hematopoietic function of the bone marrow gradually becomes affected, leading to a series of symptoms such as fever, infection, bleeding, anemia, and multiple organ dysfunction, and even death."Currently, the cure for leukemia relies heavily on the transplantation of healthy hematopoietic stem cells, and non-relative hematopoietic stem cell matching usually requires a very long waiting time, causing patients to miss effective treatment opportunities," said Zhao Jiawei.In light of this, the research team proposed an idea that some congenital familial hereditary risk factors may play an important role in the pathogenesis of leukemia. "Although scientists have had a fairly comprehensive understanding of the occurrence and related pathogenic mechanisms of leukemia and other hematologic malignancies in recent decades, the understanding of the role of genetic factors in hematologic malignancies is still very limited," said Zhao Jiawei.The development and improvement of high-throughput sequencing technology have brought more possibilities for population genetics research. At the end of 2020, Zhao Jiawei and his team used the UK Biobank's genetic information from over 460,000 patients to analyze the whole-genome genetic information and found highly correlated genetic risk factors in families. Ultimately, the research team identified a previously unreported gene, CTR9, which significantly increases the incidence of myeloid leukemia.
"The entire research process can be divided into two steps: finding and validating. The first step is finding the relevant gene mutation, and the second step is validating whether this mutation causes leukemia," said Zhao Jiawei."After proposing the idea, the first issue we needed to address was the statistical power, to see if the statistical data could support such a large sample size. After solving the statistical challenges, the research team found rare gene mutations through whole-genome sequencing and conducted association studies, ultimately pinpointing an important familial risk factor for myeloid hematologic malignancies," Zhao Jiawei said.The expansion of hematopoietic stem cells is an early manifestation of leukemia. After excessive expansion, some hematopoietic stem cells may gradually lose their self-regulation and differentiation abilities into normal blood cells, eventually leading to cancer. Using immunodeficient mice as models, the research team validated the impact of this risk factor on hematopoietic stem cells, revealing the biological mechanisms by which this high-risk pathogenic factor leads to leukemia.In over two years of subsequent validation experiments, the research team found that only partial deletion of CTR9 significantly expands both long-term and short-term hematopoietic stem cells, while complete deletion of CTR9 prevents long-term maintenance of hematopoietic stem cells. It is worth noting that compared to other more common genetic factors, this gene mutation increases susceptibility to leukemia by tenfold.In addition, fusion genes are the main indicators for diagnosis, prognosis stratification, targeted therapy, and monitoring of minimal residual disease in leukemia. Currently, hundreds of fusion genes have been included in the World Health Organization's classification criteria for leukemia diagnosis. "There are many specific fusion genes that can cause leukemia, and this gene mutation we discovered belongs to the genes that affect the occurrence of leukemia through a class of fusion genes," Zhao Jiawei said."The research team used a series of impressive cutting-edge genomics and epigenomics technologies as well as rigorous molecular biology analyses to dissect the function of this novel pathogenic factor in self-renewal regulation of human hematopoietic stem cells and susceptibility to leukemia," commented
"Young" Cancer
Unlike most other malignant tumors, leukemia is a "young" malignancy with an average onset age significantly lower than other solid malignancies. According to the "National Childhood Cancer Monitoring Annual Report (2022)" compiled by the National Children's Tumor Monitoring Center, leukemia remains the most common cancer in Chinese children.Acute leukemia is characterized by its rapid onset, high mortality rate, and difficulty in complete cure. As leukemia cells proliferate and accumulate uncontrollably in the bone marrow, the normal hematopoietic function of the bone marrow gradually becomes affected, leading to a series of symptoms such as fever, infection, bleeding, anemia, and multiple organ dysfunction, and even death."Currently, the cure for leukemia relies heavily on the transplantation of healthy hematopoietic stem cells, and non-relative hematopoietic stem cell matching usually requires a very long waiting time, causing patients to miss effective treatment opportunities," said Zhao Jiawei.In light of this, the research team proposed an idea that some congenital familial hereditary risk factors may play an important role in the pathogenesis of leukemia. "Although scientists have had a fairly comprehensive understanding of the occurrence and related pathogenic mechanisms of leukemia and other hematologic malignancies in recent decades, the understanding of the role of genetic factors in hematologic malignancies is still very limited," said Zhao Jiawei.The development and improvement of high-throughput sequencing technology have brought more possibilities for population genetics research. At the end of 2020, Zhao Jiawei and his team used the UK Biobank's genetic information from over 460,000 patients to analyze the whole-genome genetic information and found highly correlated genetic risk factors in families. Ultimately, the research team identified a previously unreported gene, CTR9, which significantly increases the incidence of myeloid leukemia.
Identification of a New Genetic Pathogenic Factor
Identifying a new genetic pathogenic risk factor for leukemia from over 460,000 patient samples is no easy task. The human genome consists of over 3 billion base pairs and nearly 30,000 genes, making finding gene mutations in this vast genome like finding a needle in a haystack."The entire research process can be divided into two steps: finding and validating. The first step is finding the relevant gene mutation, and the second step is validating whether this mutation causes leukemia," said Zhao Jiawei."After proposing the idea, the first issue we needed to address was the statistical power, to see if the statistical data could support such a large sample size. After solving the statistical challenges, the research team found rare gene mutations through whole-genome sequencing and conducted association studies, ultimately pinpointing an important familial risk factor for myeloid hematologic malignancies," Zhao Jiawei said.The expansion of hematopoietic stem cells is an early manifestation of leukemia. After excessive expansion, some hematopoietic stem cells may gradually lose their self-regulation and differentiation abilities into normal blood cells, eventually leading to cancer. Using immunodeficient mice as models, the research team validated the impact of this risk factor on hematopoietic stem cells, revealing the biological mechanisms by which this high-risk pathogenic factor leads to leukemia.In over two years of subsequent validation experiments, the research team found that only partial deletion of CTR9 significantly expands both long-term and short-term hematopoietic stem cells, while complete deletion of CTR9 prevents long-term maintenance of hematopoietic stem cells. It is worth noting that compared to other more common genetic factors, this gene mutation increases susceptibility to leukemia by tenfold.In addition, fusion genes are the main indicators for diagnosis, prognosis stratification, targeted therapy, and monitoring of minimal residual disease in leukemia. Currently, hundreds of fusion genes have been included in the World Health Organization's classification criteria for leukemia diagnosis. "There are many specific fusion genes that can cause leukemia, and this gene mutation we discovered belongs to the genes that affect the occurrence of leukemia through a class of fusion genes," Zhao Jiawei said."The research team used a series of impressive cutting-edge genomics and epigenomics technologies as well as rigorous molecular biology analyses to dissect the function of this novel pathogenic factor in self-renewal regulation of human hematopoietic stem cells and susceptibility to leukemia," commented
