Blood blockbuster: Sun Shaocong's team reveals a new mechanism for DYRK1A to regulate acute B lymphocytic leukemia

Acute lymphocytic leukemia (ALL) is the most common hematological malignancy in children.
In recent years, with the improvement of diagnostic classification techniques, combined chemotherapy and the application of new immunotherapies, the long-term survival rate has reached 80%, but relapse and refractory B Acute lymphocytic leukemia (B-ALL) is still an important cause of childhood leukemia-related mortality.
Therefore, relapsed and refractory B-ALL urgently needs new treatment methods
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On July 15, 2021, Professor Sun Shaocong's research group from the Department of Immunology of MD Anderson Cancer Center in the United States published the title: DYRK1a mediates BAFF-induced noncanonical NF-κB activation to promote autoimmunity and The latest research results of B cell leukemogenesis
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This study clarified that dual-specific tyrosine phosphorylation-regulated kinase 1a (DYRK1a) interacts with tumor necrosis factor receptor acting factor 3 (TRAF3) and mediates its phosphorylation, thereby promoting the non-canonical NF-κb signaling pathway.
Activation, which in turn affects the occurrence and development of this disease, provides new concepts and drug targets for the treatment of this disease
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Nuclear factor-κB (Nuclear factor-κB, NF-κB) is a type of transcription factor widely present in various types of cells, because it can bind to the κ-chain gene enhancer κB sequence of immunoglobulin when it was first discovered in 1986 It was named NF-κB
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NF-κB transcription factors can be activated by a variety of signals, including cytokines, pathogens, and other stress conditions, which in turn affect cell growth, apoptosis, development and canceration
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In addition, abnormally activated NF-κB is often accompanied by abnormally activated NF-κB in many chronic inflammations, autoimmune diseases and tumor tissues.
Therefore, in-depth study of NF-κB activation and its regulatory mechanism can provide new strategies and approaches for the treatment of many major diseases
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The BAFF-mediated non-canonical NF-κb signaling pathway NF-κB family proteins have two main activation pathways, namely the classic and non-canonical NF-κB signaling pathways
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The common feature of the two pathways is that TNF receptor-associated facto (TRAF) is used as the key adaptor protein and the two cascades are regulated by activating IκB kinase (IKK).
Complex
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Compared with the classic NF-κB signaling pathway, the non-canonical NF-κB signaling pathway has a slower transduction but a longer duration; it phosphorylates IKKα by activating NF-κB-inducible kinase (NIK), and then phosphorylates p100 The phosphorylated p100 is recognized by the SCF-β TrCP E3 complex and ubiquitinated
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After the p100 protein is modified by the ubiquitination pathway, the proteasome will degrade the ANK-containing C-terminus without affecting the RHD-containing N-terminus (that is, the p52 subunit).
This process is also known as p100 processing
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Finally, p52 combines with RelB to form a dimer, which transfers into the nucleus and activates the transcription of target genes
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Professor Sun Shaocong’s group has long been engaged in the research of non-classical NF-kb signaling pathways
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In this work, the team discovered for the first time another important new member of this signaling pathway, DYRK1a
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The study found that DYRK1a can directly bind to TRAF3, and phosphorylates the 29th serine or threonine on TRAF3 under BAFF stimulation, which promotes the enrichment of NIK protein and activates the non-canonical NF-kb signaling pathway
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More importantly, they found that abnormally activated non-classical NF-κB signaling pathways play an important role in increasing the proliferation of B-ALL tumor cells and anti-apoptosis by regulating the expression of downstream target genes (Bcl-2 and Bcl-XL)
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The relationship between the expression of DYRK1A and Bcl-XL genes and the prognosis of patients with B-line acute lymphoblastic leukemia The DYRK1A coding gene is located in the key region of Down Syndrome Critical Region (DSCR) on human chromosome 21, in which Down Syndrome Patients with acute lymphoblastic leukemia and B-line acute lymphoblastic leukemia with internal amplification of chromosome 21 (iAMP21) have a poor prognosis and a high recurrence rate
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At present, we are not fully aware of the reasons why children with Down syndrome and iAMP21 suffer from a poor prognosis and a high recurrence.
This study provides a reasonable explanation for the above-mentioned key problem.
The DYRK1A gene is used in such leukemia patients.
Abnormal copy increase and high expression in B-ALL are very important for the survival of B-ALL, which in turn will reduce the viability of cancer cells
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Genome abnormalities of DYRK1a gene in childhood acute lymphoblastic leukemia.
It is reported that Professor Sun Shaocong from the Department of Immunology of MD Anderson Cancer Center in the United States is the corresponding author of the paper, and Dr.
Yanchuan Li is the first author of the paper
.

Link to the paper: https://doi.
org/10.
1182/blood.
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