1.Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia.
Jianfeng LI ; Yuting DAI ; Liang WU ; Ming ZHANG ; Wen OUYANG ; Jinyan HUANG ; Saijuan CHEN
Frontiers of Medicine 2021;15(3):347-371
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as DUX4 rearrangements, MEF2D rearrangements, ZNF384/ZNF362 rearrangements, NUTM1 rearrangements, BCL2/MYC and/or BCL6 rearrangements, ETV6-RUNX1-like gene expression, PAX5alt (diverse PAX5 alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic PAX5 alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.
B-Lymphocytes
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Humans
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Mutation
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Oncogene Proteins, Fusion/genetics*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
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Precursor Cell Lymphoblastic Leukemia-Lymphoma
2.Progress of studies on genetics of childhood acute leukemia.
Journal of Experimental Hematology 2013;21(3):791-795
This study on determination of leukemia-specific chromosomal abnormalities and their relationship with prognosis of childhood acute leukemia (AL) had an important significance for childhood acute leukemia. In recent years, the efficacy of treatment of childhood AL has been greatly improved, but relapse is still a main factor affecting prognosis. Treatment based on the risk stratification by cytogenetic abnormalities can improve the prognosis and survival rate. In the past 3 decades, the genetic techniques have developed rapidly and many new genetic abnormalities have been found. This review highlights the main chromosomal and genomic abnormalities of 3 common childhood AL, including B-cell precursor acute lymphoblastic leukemia (BCP-ALL), T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
Acute Disease
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Child
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Humans
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Leukemia
;
genetics
;
Leukemia, Myeloid, Acute
;
genetics
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
;
genetics
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
;
genetics
3.Clinical Study on the Relationship between Gene Mutation Profile and Prognosis in Pediatric Acute Lymphocyte Leukemia.
Yan CHEN ; Shan-Shan QI ; Li-Li DING ; Yu DU ; Na SONG ; Zhuo WANG ; Li YANG ; Ming SUN ; Hao XIONG
Journal of Experimental Hematology 2023;31(1):17-24
OBJECTIVE:
To analyze the gene mutation profile in children with acute lymphocyte leukemia (ALL) and to explore its prognostic significance.
METHODS:
Clinical data of 249 primary pediatric ALL patients diagnosed and treated in the Department of Hematological Oncology of Wuhan Children's Hospital from January 2018 to December 2021 were analyzed retrospectively. Next-generation sequencing (NGS) was used to obtain gene mutation data and analyze the correlation between it and the prognosis of children with ALL.
RESULTS:
227 (91.2%) were B-ALL, 22 (8.8%) were T-ALL among the 249 cases, and 178 (71.5%) were found to have gene mutations, of which 85 (34.1%) had ≥3 gene mutations. NRAS(23.7%), KRAS (22.9%),FLT3(11.2%), PTPN11(8.8%), CREBBP (7.2%), NOTCH1(6.4%) were the most frequently mutated genes, the mutations of KRAS, FLT3, PTPN11, CREBBP were mainly found in B-ALL, the mutations of NOTCH1 and FBXW7 were mainly found in T-ALL. The gene mutation incidence of T-ALL was significantly higher than that of B-ALL (χ2= 5.573,P<0.05) and were more likely to have co-mutations (P<0.05). The predicted 4-year EFS rate (47.9% vs 88.5%, P<0.001) and OS rate (53.8% vs 94.1%, P<0.001) in children with tp53 mutations were significantly lower than those of patients without tp53 mutations. Patients with NOTCH1 mutations had higher initial white blood cell count (128.64×109/L vs 8.23×109/L,P<0.001), and children with NOTCH1 mutations had a lower 4-year EFS rate than those of without mutations (71.5% vs 87.2%, P=0.037).
CONCLUSION
Genetic mutations are prevalent in childhood ALL and mutations in tp53 and NOTCH1 are strong predictors of adverse outcomes in childhood ALL, with NGS contributing to the discovery of genetic mutations and timely adjustment of treatment regimens.
Child
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Humans
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics*
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Cell Cycle Proteins/genetics*
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Proto-Oncogene Proteins p21(ras)/genetics*
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Retrospective Studies
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Ubiquitin-Protein Ligases/genetics*
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Prognosis
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Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
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Mutation
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Lymphocytes
4.Clinical analysis of long-term survival and influencing factors of chimeric antigen receptor T-cell therapy in relapsed/refractory acute B-cell lymphoblastic leukemia.
Yi WANG ; Qiu Ying GAO ; Hui WANG ; Ding ZHANG ; Ying GAO ; Ying Di MIAO ; Xin Hui ZHAI ; Xing Xing HU ; Xin Li RU ; Wei Hua ZHANG
Chinese Journal of Hematology 2023;44(10):800-804
Objective: To analyze the survival and influencing factors of chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL) . Methods: Clinical information of patients who received CAR-T-cell therapy and achieved complete remission of R/R B-ALL between May 2015 and June 2018 at the Shaanxi Provincial People's Hospital was obtained. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and leukemia-free survival (LFS) times of patients, and Cox regression analysis was performed to analyze the prognostic factors that affect patient survival after CAR-T therapy. Results: Among the 38 patients with R/R B-ALL, 21 were men, with a median age of 25 (6-59) years and a median OS time of 18 (95% CI 3-33) months. Multivariate Cox regression analysis showed that positive MLL-AF4 fusion gene expression was an independent risk factor for OS and LFS (OS: HR=4.888, 95% CI 1.375-17.374, P=0.014; LFS: HR=6.683, 95% CI 1.815-24.608, P=0.004). Maintenance therapy was a protective factor for OS and LFS (OS: HR=0.153, 95% CI 0.054-0.432, P<0.001; LFS: HR=0.138, 95% CI 0.050-0.382, P<0.001). In patients with MRD negative conversion, LFS benefit (HR=0.209, 95% CI 0.055-0.797, P=0.022) and OS difference was statistically insignificant (P=0.111). Moreover, patients with high tumor burden were risk factors for OS and LFS at the level of 0.1 (OS: HR=2.662, 95% CI 0.987-7.184, P=0.053; LFS: HR=2.452, 95% CI 0.949-6.339, P=0.064) . Conclusion: High tumor burden and high-risk genetics may affect the long-term survival rate of patients with R/R B-ALL receiving CAR-T, and lenalidomide-based maintenance therapy may improve their prognosis.
Male
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Humans
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Adult
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Middle Aged
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Female
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Receptors, Chimeric Antigen/genetics*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics*
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Immunotherapy, Adoptive
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
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Cell- and Tissue-Based Therapy
5.Immunophenotypic and Clinical Characteristics of SET-CAN Fusion Gene Positive Acute Leukemia Patients.
Song-Ya LIU ; Li ZHU ; Chun-Yan WANG ; Cheng HE ; Shu-Juan YI ; Li MENG ; Min XIAO ; Xia MAO
Journal of Experimental Hematology 2023;31(6):1639-1646
OBJECTIVE:
To analyze the flow immunophenotype and clinical characteristics of leukemia patients with positive SET-CAN fusion gene.
METHODS:
A total of 7 newly diagnosed acute leukemia patients with SET-CAN fusion gene admitted to Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology from February 2016 to February 2020 were collected. Multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect the expression of SET-CAN fusion gene. The immunophenotype was detected by four-color flow cytometry. The case information of 17 literatures published at home and abroad was extracted for statistical analysis.
RESULTS:
Among the 7 patients, 2 cases were diagnosed as mixed phenotype acute leukemia (MPAL), 2 cases as acute myeloid leukemia (AML), and 3 cases as T-acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). Leukemia cells in bone marrow specimens of all cases expressed or partially expressed CD34, CD33 and CD7. CD5 and cytoplasmic CD3 were expressed in 5 patients except 2 patients diagnosed with AML. Bone marrow and lymph node specimens were both detected in 2 patients, and the immunophenotypes of the two specimens were not completely consistent, with differences in lineage or maturity related markers. Two patients with MPAL showed differentiated response to treatment. One AML patient gave up treatment, and another AML patient with FLT3-ITD gene mutation had a poor prognosis. All three T-ALL/LBL patients maintained a long duration of remission after induced remission, and one case underwent allogeneic hematopoietic stem cell transplantation.
CONCLUSIONS
There are common characteristics of immunophenotype in patients with positive SET-CAN fusion gene. Differential expression of immunophenotype in samples from different parts is observed in some cases. The prognosis of these diseases varies.
Humans
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Leukemia, Myeloid, Acute/pathology*
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Bone Marrow/pathology*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics*
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Antigens, CD34
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
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Immunophenotyping
6.Expressing of linc-223 and miR-125a in Patients with Acute Leukemia and Its Clinical Significance.
Journal of Experimental Hematology 2020;28(6):1819-1825
OBJECTIVE:
To determine the expression level of linc-223 and miR-125a in the patients with adult acute leukemia (AL) and explore the relationship between the expression level and the occurrence, development, prognosis of leukemia.
METHODS:
Bone marrow samples of 93 patients with AL treated in our hospital from January 2017 to September 2017 were enrolled, including 21 cases of acute lymphoblastic leukemia (ALL) and 72 cases of acute non-lymphocytic leukemia (ANLL). At the same time, bone marrow samples from 20 cases of non-malignant hematopathy patients in the same period were enrolled as control group. Real-time quantitative PCR (qRT-PCR) was used to test the expression level of linc-223 and miR-125a in bone marrow of 93 AL patients and the relationship between the level and the occurrence, development, prognosis of leukemia was analyzed.
RESULTS:
There was no significant difference in the expression of linc-223 between AL patients (ANLL and ALL) and control group (P>0.05). Moreover, there was no significant correlation between linc-223 and PML-RARα gene or the remission rate of patients after treatment. The expression of miR-125a in ANLL patients was significantly lower than those in the control group (P<0.01), but there was no significant difference between the initial treatment, recurrence and remission group (P>0.05), and also for ALL and control group (P>0.05). In the newly treatment ANLL patients, the expression level of miR-125a showed negatively correlated with LDH level and the ratio of immature cells (r=-0.454, r=-0.400), but not with sex, degree of risk, peripheral blood leukocyte count, platelet count, hemoglobin content, WT1, CRP, etc. (P>0.05). There was a positive correlation between linc-223 and miR-125a in ANLL patients (r=0.296).
CONCLUSION
No abnormal expression of linc-223 was found in the bone marrow of AL patients, but miR-125a expression shows a low level and positively correlate with the expression level of linc-223 in ANLL, which is helpful for the diagnosis.
Acute Disease
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Adult
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Humans
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Leukemia, Myeloid, Acute
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MicroRNAs
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Patients
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Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics*
8.Gene Mutation in Acute Lymphoblastic Leukemia by DNA Sequencing.
Ru-Yue ZHENG ; Shu-Juan WANG ; Chong WANG ; Tao LI ; Lin-Xiao LIAO ; Meng-Lin LI ; Sheng-Mei CHEN ; Rong GUO ; Wei-Qiong WANG ; Yu ZHANG ; Yi FAN ; Ding-Ming WAN ; Yan-Fang LIU
Journal of Experimental Hematology 2020;28(6):1791-1795
OBJECTIVE:
To analyze the characteristics of gene mutation in adult ALL and its clinical significance.
METHODS:
Clinical data of 134 primary adult ALL patients and DNA sequencing results of 16 kinds of gene mutation were collected. The characteristic of gene mutation and clinical significances were statistically analyzed.
RESULTS:
In 31 cases of 134 ALL cases (23.13%) the gene mutations were detected as follows: 19 cases of 114 B-ALL cases (16.67%), 11 cases of 19 T-ALL cases (57.89%) and 1 case of T/B-ALL. The incidence of T-ALL gene mutation was significantly higher than that of B-ALL (χ
CONCLUSION
There may be multiple gene mutations in adult ALL patients. IL7R and NOTCH1 are the most common gene mutations and NOTCH1 mutation may indicate poor prognosis. Detection of gene mutations is helpful to understand the pathogenesis of ALL and evaluate the prognosis of adult ALL patients.
Adult
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Humans
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Mutation
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Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
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Prognosis
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Receptor, Notch1/genetics*
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Sequence Analysis, DNA