The 63rd Annual Conference of Hematology (ASH) will be held on December 11-14, 2021. As the world's premier academic exchange event in the field of hematology, ASH has more than 25,000 members from nearly 100 countries, sharing and discussing innovative ideas and the latest scientific and clinical research results in hematology every year. At this conference, Lu Daopei's medical team made a stunning appearance with 2 oral reports (Oral) and 9 poster presentations (Poster), a total of 11 research results.
As a leader in China's non-public medical institutions, Lu Daopei Hospital can bring the world's most cutting-edge medical services to patients without the contribution of its molecular medicine team. The molecular medicine team has escorted the clinical precision treatment of Lu Daopei Hospital, provided accurate testing support, and obtained rich academic achievements. On this occasion, Medical Pulse sincerely invites experts from the Department of Clinical Laboratory of Lu Daopei Hospital to be interviewed to share their recent research progress to be announced at the ASH conference.
The study of the molecular spectrum of B-cell precursor acute lymphoblastic leukemia (B-ALL) is of great significance to its diagnosis and treatment. What other research directions do you think are worth exploring in the future field of B-ALL disease?
Abstract number: 1312
Identification of new CXCR4alt subtypes and Blenk gene splicing variants in B-ALL based on transcriptome classification model and co-expression network analysis
Cao Panxiang (Bioinformatics) Researcher
B-cell precursor acute lymphoblastic leukemia (B-ALL) is a heterogeneous acute leukemia with stage-specific phenotypic and cytogenetic features. Although the study of the B-ALL molecular spectrum helps to diagnose and risk stratification, at the transcriptome level, the mechanism of leukemia onset and development remains unclear, which poses a challenge to the precise diagnosis and treatment of the disease.
1) Treatment of B-ALL requires classification of the disease. After systematic research, we found that combining machine learning and transcriptome data, B-ALL can be accurately typed, especially for cases lacking typical molecular cytogenetic features, including Ph-like, ETV6-RUNX1-like, and ZNF384-r-like subtypes. Clustering was further based on gene expression characteristics, and for the first time, candidate molecular subtypes characterized by CXCR4 alterations (CXCR4alt) were successfully isolated. This newly discovered subtype of CXCR4alt, which accounts for 2% of B-ALL cases, has unique biological characteristics with CXCR4 R334X mutation and FRNA overexpression, leading to activation of the CXCL12-CXCR4-MAPK pathway.
2) Although the classification of B-ALL is helpful for treatment, there are still many cases of molecular subtypes that are refractory to recurrence, so in-depth research is needed on the mechanism of occurrence and development of B-ALL. Through gene co-expression network (WGCNA) and transcriptional regulatory network analysis, the functional modules and transcriptional regulatory networks behind the development of B-ALL are deeply explored, and the core genes in these functional modules and networks can be used as potential therapeutic targets.
3) Abnormal splicing of gene transcription often occurs in B-ALL, and it is urgent to explore its shear form to help B-ALL targeted therapy. We found that splicing variants of BRNK gene are common in B-ALL patients with specific subtypes, including BCR-ABL1, ETV6-RUNX1, etc., while subtypes characterized by pre-BCR signal activation, such as TCF3-PBX1 and MEF2D-r, splicing variants without BRNK suggest that the sheared form of BRNK gene can assist in discovering whether pre-BCR signals are activated, and thus assist in B-ALL targeted therapy.
With the development of molecular biology technologies such as second-generation gene sequencing technology, AML diagnosis and treatment has made great progress. Can you share your research in recent years in AML diagnosis and treatment?
Abstract number: 2243
Arrhyth expression of DNTT in AML, gene-length mutations promoted by TdT activation, and their correlation with transplant prognosis for ATG-containing pretreatment protocols
Dr. Zhou Xiaosu
With the advancement of technology and the reduction of cost, gene high-throughput sequencing (NGS), that is, second-generation sequencing, is increasingly used in the clinical diagnosis and treatment of blood diseases. Compared with one-generation sequencing, NGS can not only find more low-frequency mutations, but also detect multiple genes at the same time, facilitating a more comprehensive understanding of the molecular genetics of tumors.
AML is a very heterogeneous hematological tumor, and molecular genetic studies have identified some genes related to AML prognosis stratification, such as FLT3-ITD, NPM2, RUNX1, CEBPA bialele, etc. Risk levels can be made according to the type of genetic mutation, but there are still large differences in survival in individuals with the same risk level, so the classification of genetic mutations requires more in-depth and detailed study.
The study we published in the ASH abstract explores the relationship between the micro-homologous recombination (MMRDR) mechanism of DNTT abnormal expression and TdT (DNTT coding) activation in AML and gene length mutation (LM) on the basis of NGS, and its correlation with prognosis.
A total of 578 AML patients were included in the study, and through the analysis of gene LM types, it was found that among the types containing non-template addition sequences, the addition sequences had the characteristics of high GC content, and the sequence length was positively correlated with the GC content. Combined with gene expression data obtained by transcriptome sequencing (RNA-seq), abnormally high expression of DNTT was found in patients with LM types of genes with possible involvement in TdT activation. These evidences show that as gono-specifically expressed TdT, the MDRR mechanism mediated by its abnormal activation in AML plays a role in the gene LMs of these patients. We also found the same pattern in FLT3, which has the highest overall incidence of gene LM. Patients containing FLT3 LM-III (with non-template addition sequences) have significant high DNTT expression. We conducted prognosis analysis of 239 AML patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) containing antithymocytopoietin (ATG) pretreatment regimen and found that patients with FLT3 LM-III mutations had a better prognosis with ATG-treated allo-HSCT, suggesting that ATG may have an antitumor effect in some AML patients with abnormal expression of gonorrhea antigens.
Therefore, the NGS-based tumor gene mutation Panel screening, combined with the gene expression data obtained by RNA-seq, helps to provide more information on clinical diagnosis and prognosis.
The use of all-trans tretinoin (ATRA) and arsenic greatly improved the prognosis of acute promyelocytic leukemia (APL), but relapse persisted. In your study, what about recurrence and drug-resistant mutations in patients treated with all-trans retinoids and arsenic?
Abstract number: 2367
Analysis of relapse and PML-RARA fusion gene resistance mutations in patients with acute promyelocytic leukemia
Dr. Jiaqi Chen
Although regimens based on all-trans retinoids (ATRA), arsenic, and chemotherapy have enabled significant efficacy and long-term survival in patients with acute promyelocytic leukemia (APL), some patients still experience relapse or drug resistance. To this end, we have studied APL recurrence, secondary tumors and the appearance of drug-resistant mutations during treatment.
The study retrospectively analyzed the 40 APL patients admitted to our hospital between January 2013 and July 2020. Although patients with APL achieved high remission rates and long-term survival, there were still 3 patients with secondary tumors. The eight patients with initial onset and one patient with APL in remission achieved sustained remission with triple therapy (ATRA, arsenic, and chemotherapy) and no PML-RARA resistance mutations were detected. Another 28 cases of APL came to our hospital after relapse, and 9 of them detected PML-RARA resistance mutations.
The study further highlights the importance of standardized treatment for APL patients: adherence to systematic and standardized treatment is necessary to achieve rapid remission and reduce recurrence. The disease progression caused by drug-resistant mutations in a small number of patients can be seen that while standardizing the treatment of APL, attention should also be paid to the treatment itself and the secondary tumor caused by the patient's congenital genetic factors.
TCF3-HLF positive B-ALL is rare and the prognosis is extremely poor. Can you tell us about your progress in TCF3-HLF-positive B-ALL treatment?
Abstract number: 2387
Clinical and molecular characteristics of patients with TCF3-HLF-positive B-ALL - analysis of 24 patients in a single center
Dr. Xue Chen
Companion t (17; 19)(q22; P13) Chromosomal translocation or B-ALL positive for the TCF3-HLF fusion gene is very rare and has a very poor prognosis. Over the past eight years, we have found a total of 24 patients carrying the TCF3-HLF fusion gene in more than 3,000 B-ALL patients, the largest case of the disease in this group to date.
We reported in detail on the molecular characteristics (including fusion forms, karyotypes, immunophenotypings, genetic mutations) and clinical treatment and outcomes of this group of patients. The median overall survival (OS) of 24 patients was 18.5 months (6-75 months). Thirteen patients received allo-HSCT with a median OS of 23 months (13-75 months), of which 8 were in complete remission (CR) until the end of follow-up. Eleven patients did not receive allo-HSCT, the median OS was 9 months (6-29 months), of which 7 died, 3 relapsed and then induced failure, and only 1 was in CR status for 19 months by the end of follow-up. Twelve patients received CAR-T therapy, of which 9 achieved CR and bridged allo-HSCT after CAR-T treatment.
Although patients with B-ALL who are positive for TCF3-HLF fusion gene have a very poor prognosis, timely use of CAR-T plus allo HSCT may improve efficacy in these patients.
epilogue
The annual ASH Annual Conference is the world's top academic conference in the field of blood diseases. Lu Daopei Hospital has been shortlisted for the ASH Annual Meeting for consecutive years, which fully demonstrates its academic achievements in the industry, and also reflects the recognition of lu Daopei's medical team by the authority in the field of global hematology, and its excellent experimental results have been widely praised by the international hematology community. It is hoped that this "Chinese force" will continue to explore, lead Chinese medicine to the top of the world's academia, and benefit more patients with blood diseases.
Note: Rankings are in no particular order and are written in summary number order.
Panxiang Cao (Bioinformatics) Researcher
B.S. in Bioinformatics, Master of Pharmacology, Laboratory Technician, Assistant Researcher, Deep Learning Development and Application Engineer (Senior)
He is engaged in the clinical translational research of hematological system-related tumors and genetic diseases, and actively explores and promotes the application of new biotechnology and bioinformatics technologies in the molecular diagnosis of blood diseases. Responsible for the construction, maintenance and update of the laboratory's second-generation sequencing (NGS) analysis process and platform, including multi-gene panel detection and omics analysis based on whole exome, whole genome and transcriptome sequencing. Based on the big data of hematological tumors and genetic diseases, he has carried out systematic multi-omics integrated analysis, and has rich practical and research experience in the field of molecular diagnosis of blood diseases.
The corresponding research results have been reported and exchanged at the Annual Meeting of the American Human Genetics Society (ASHG) and the American Annual Conference of Hematology (ASH). He is a member of the American Society of Hematology (ASH), a member of the Chinese Society of Biological Engineering, and a member of the Molecular Diagnostic Expert Committee of the Chinese Society of Integrative Medicine.
One of the main members of the genomics analysis team of the Molecular Medicine Laboratory.
Dr. Xiaosu Zhou
Assistant researcher of Beijing Lu Daopei Institute of Hematology
Member of the Laboratory Medicine Professional Committee of the Beijing Association of Non-public Medical Institutions
Postdoctoral Fellow, Chinese Academy of Medical Sciences, Ph.D., Ocean University of China. After leaving the postdoctoral station, he joined Lu Daopei's molecular medicine team, and then transferred to the Institute of Hematology to be responsible for scientific research project development. He is mainly engaged in the research and development of immunotherapy technology and molecular diagnostic technology related to hematological tumors, as well as the research of gene mutation mechanism, and has rich experience in molecular diagnosis and pathogenic mechanism research. He is committed to the study of the molecular pathogenesis of tumors in the blood system and the application of cell therapy technology based on tumor neoantigens in acute leukemia.
He has published academic papers as the first author in SCI journals such as The Journal of Infectious Diseases, Plos Neglected Tropical Diseases, and Frontiers in Microbiology.
Dr. Jiaqi Chen
Assistant researcher and clinical pharmacist in the Department of Molecular Medicine, Department of Pathology and Medical Laboratory
Ph.D. in Pharmacology, Jilin University
One of the main members of the genomics analysis team of the Molecular Medicine Laboratory
He is a member of the American Haematology Annual Meeting (ASH), the Japan Hematology Society Annual Meeting (JSH), the Korean Oncology Society Annual Meeting (KCA), and the International Laboratory Hematology Association Annual Meeting (ISLH).
He is a member of the Molecular Diagnosis Committee of the Medical Laboratory Committee of the Chinese Association of Integrative Traditional and Western Medicine, and a member of the Experimental Diagnosis Committee of Hematological Diseases
Member of the Medical Laboratory Quality Management Committee of China Sinopharm Quality Management Association
He is a member of the Chinese Pharmacological Society, a member of the Chinese Pharmaceutical Society, and a member of the Chinese Anti-Cancer Association
In 2017, he joined Lu Daopei's molecular medicine team and engaged in pharmacogenomic testing, report interpretation and personalized medication guidance and consultation. He is committed to the research of personalized drugs and pharmacogenomics for hematological diseases. Responsible for drug guidance for patients with hematological tumors and targeted therapy drug resistance mutation detection projects.
Dr. Xue Chen
Deputy director of the Laboratory Department of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, laboratory physician, assistant researcher, genetic consultant
Ph.D. in Hematology, Peking University Medical College, has won the Peking University Academic Innovation Award and the National Scholarship for Doctoral Students of the Ministry of Education. After graduating with a doctorate, he joined Lu Daopei's molecular medicine team, one of the main members of the genomics analysis team of the Molecular Medicine Laboratory, and was responsible for the application and continuous improvement of the blood system genetic disease project and the fusion gene project. He has rich project experience in analyzing and summarizing the results of more than 20,000 cases of fusion gene screening and the results of transcriptome sequencing of more than 1,000 cases of acute leukemia.
As the first author, he has published more than 20 academic papers in Nature Medicine, Blood Cancer Journal, British Journal of Cancer, British Journal of Haematology, Cancer Gene Therapy, Clinical Genetics and other journals.