Cancer Communications Meng Guoyu/Huang Jinyan/Chen Zhu/Hu Weiguo made new breakthroughs in the pathogenesis of B-cell acute lymphoblastic leukemia

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Homeobox genes exist in almost all multicellular animals.
The homology domain encoded by the homeobox gene is a binding domain that specifically recognizes the target gene sequence.
It is mainly used as a transcription factor to play a gene regulation function and can be used accurately.
Recognize and regulate target genes within the space-time range
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DUX4 (Double Homeobox 4) belongs to the double homeobox transcription factor family, and its homology domain is composed of HD1 and HD2
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DUX4 is an important switch molecule in the embryonic development stage.
Its active expression in embryonic stem cells can activate the embryonic genome, but its abnormal expression and activation in myoblasts will promote cell apoptosis and eventually lead to facial scapulohumeral muscular dystrophy ( FSHD) happened
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In addition, the DUX4 fusion oncoprotein DUX4/IGH (which lacks the C-terminus of DUX4) formed by inserting the DUX4 gene sequence into the immunoglobulin heavy chain (IGH) on chromosome 14 has become the main cause of juvenile acute lymphoblastic leukemia.
Therefore, clarifying the regulation and molecular mechanism of DUX4 under normal and carcinogenic conditions will help to better guide clinical biochemical diagnosis and precise molecular biological treatment
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The Shanghai Institute of Hematology has achieved fruitful scientific research results and a high international academic status in the field of leukemia for more than 20 years
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The case of ATRA and ATO co-targeting successfully cured APL has become a model in the industry, and the 5-year disease-free survival rate has reached 85%.

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There are also extraordinary results in other types of leukemia (AML, ALL, CML, etc.
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Most of these results have been widely used clinically, and have accumulated a valuable knowledge base for basic research
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Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Meng Guoyu’s team based on the treasure house accumulated by these predecessors, and opened up new research roads to "clinical needs, clinical "Transformation" is an idea, with the spirit of sitting on the bench, committed to solving clinical problems through basic research, practicing practice, and in-depth research (Figure 1)
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Figure 1: Based on the platform background and accumulation, Meng Guoyu and other teams opened up a series of systematic work for new research roads
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In the field of B-ALL and APL, starting from the clinical needs, he constantly put forward his own unique thinking and understanding (bold hypothesis), and finally committed to clinical translation and clinical practical problem solving (careful verification)
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Over the years, a series of systematic research work has been carried out on the pathogenesis of B-ALL (Figure 2): The structure of the DUX4-DNA complex was analyzed for the first time in the world, and DUX4/IGH was verified at the functional level.
The effect of an oncoprotein on the transcriptional activation of downstream target genes and the inhibition of B cell differentiation and proliferation (Dong et al, Leukemia, March 2018), for the first time at the atomic level revealed a new mechanism for DUX4/IGH to recognize and bind target genes ( Dong et al, Leukemia, September 2018), these findings not only deepen people's understanding of the molecular mechanism of leukemia, but also provide a theoretical basis and therapeutic targets for clinical targeted therapy
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In order to fully reveal the "hard bone" of the molecular pathogenesis of this type of leukemia, the team continued to work hard on the basis of the previous work, and tried hard and failed repeatedly
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Figure 2: Meng Guoyu and other teams in the field of DUX4/IGH type acute lymphoblastic leukemia, starting from clinical problems, continue to deepen the systemic continuity of breakthroughs
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On October 26, 2021, a new breakthrough was finally made in the mechanism of DUX4/IGH in promoting the occurrence and development of B lymphocytic leukemia (B-ALL).
"Required for oncogenic splicingin leukemia" was published online in Cancer Communications (IF=10.
39)
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This study explains for the first time how high expression of fusion genes leads to genome instability, which in turn causes the molecular mechanism of abnormal oncogenic splicing to produce downstream abnormal transcripts (such as the second-strike leukemia event ERGalt), which further deepens the understanding of this type of leukemia.
It provides a new direction for future clinical transformation and treatment
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Figure 3: DUX4//IGH-induced intron retention events (model of carcinogenic splicing mechanism) identified in B-ALL patients and the crystal structure of DUX41-150-DNAERG reveals a new DNA cross-linking mechanism for DUX4/IGH
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(A) DUX4/IGH mediates the biogenesis of ERGalt in the second blow event of leukemia.
The DRE repeat site on the ERG gene is marked with a "*"
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(B) Abnormal transcripts of downstream target genes produced by the high expression of DUX4 in newly discovered B-ALL patients, and the relative expression of the abnormal transcripts were detected by real-time fluorescent quantitative PCR
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(C) The crystal structure of DUX41-150-DNAERG complex shows a new DNA cross-linked conformation
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This research is a new breakthrough in the collaboration of Meng Guoyu/Huang Jinyan/Chen Zhu/Hu Weiguo to promote clinical transformation by expounding the pathogenesis of DUX4/IGH type leukemia
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The article uses bioinformatics to further excavate clinical data, and identifies abnormal transcripts CLEC12Aalt and C6orf89alt caused by DUX4//IGH in patients with B-ALL that may be related to the pathogenesis of leukemia, and reported in DUX4/IGH types There are intron retention events that contain repeated DRE-DRE sites in leukemia patients
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Subsequently, through the unrevealed double homeobox domain of DUX4/IGH and the cross-linked complex structure from B-ALL endogenous gene ERG, it was shown from the atomic level that DUX4/IGH recognized multiple DRE sites and produced The molecular mechanism of the above-mentioned abnormal transcripts (Figures 2 and 3); and reveals a new model of dynamic binding between DUX4/IGH and DNA, which is different from the past, and provides new insights into the pathogenesis of DUX4/IGH leukemia
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In addition, the research group also found that the DUX4/IGH and DNA complex recruited RAG1/2 to the DRE-DRE site through a cross-linked conformation, which in turn catalyzed the cleavage/recombination and oncogenic splicing of V(D)J-like in leukemia.
This is the cause of abnormal transcripts of its downstream target genes (Figure 2)
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Through long-term analysis and statistics on the survival of clinical B-ALL patients, the team combined the results of experimental theory and clinical practice to systematically reveal the molecular mechanism of DUX4/IGH type leukemia, and unearthed a batch of The prognostic stratification of types of leukemia also has a guiding prognostic molecule, which has a very positive guiding significance for the improvement of clinical guidance theories and diagnosis and treatment plans for various types of leukemia
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This study further explained the molecular mechanism of DUX4/IGH, an oncoprotein causing the pathogenesis of this type of B-ALL, on the basis of previous studies.
The treatment of this type of leukemia provides new directions and ideas
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Professor Meng Guoyu, Professor Huang Jinyan of Zhejiang University School of Medicine, Professor Chen Zhu, and Professor Hu Weiguo of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine are the co-corresponding authors of this article, Ruijin Hospital postdoctoral fellow Zhang Hao, master student Cheng Nuo, doctoral student Li Zhihui and master student Bai Ling is the co-first author
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This research was supported by the National Natural Science Foundation of China, Shanghai Gaofeng Plateau Project, Shanghai Oriental Scholars, Shanghai Guangci Translational Medicine Research and Development Foundation and other projects, and received the Shanghai Synchrotron Radiation Source (BL17U/18U/19U) Staff assistance in data collection and analysis
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Meng Guoyu team reference materials: 1.
Zhang H, Cheng N, Li Z, Bai L, Fang C, Li Y,et al.
DNA crosslinking and recombination-activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia.
Cancer Commun(Lond).
2021.
2.
Dong X, Zhang H, Cheng N, Li K, Meng G.
DUX4HD2-DNAERG structure reveals new insight into DUX4-Responsive-Element.
Leukemia.
2019;33(2): 550-3.
3.
Dong X, Zhang W, Wu H, Huang J, Zhang M, WangP, et al.
Structural basis of DUX4/IGH-driven transactivation.
Leukemia.
2018;32(6):1466-76.
4.
Wang P, Benhenda S, Wu H,Lallemand-Breitenbach V, Zhen T, Jollivet F, et al.
RING tetramerization is required for nuclear body biogenesis and PML sumoylation.
Naturecommunications.
2018;9(1):1277.
5.
Li Y, Ma X, Chen Z , Wu H, Wang P, Wu W, et al.
B1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis.
Nature communications.
2019;10(1):3789.
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Li Y, Ma X, Meng G.
PML nuclear bodybiogenesis and oligomerization-driven leukemogenesis.
Blood Science.
2020;2(1):7-10.
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Li Y, Ma X, Wu W, Chen Z, Meng G.
PML NuclearBody Biogenesis, Carcinogenesis, and Targeted Therapy.
Trends Cancer.
2020;6(10):889-906.
Original link: https://onlinelibrary.
wiley.
com/doi/10.
1002/cac2.
12234