Loss of
            <i>runx1</i>
            function results in B cell immunodeficiency but not T cell in adult zebrafish

Chi, Yali; Huang, Zhibin; Chen, Qi; Xiong, Xiaojie; Chen, Kemin; Xu, Jin; Zhang, Yiyue; Zhang, Wenqing

doi:10.1098/rsob.180043

Cited by 14 publications

(12 citation statements)

References 65 publications

(91 reference statements)

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“…Notably the zebrafish genome used for comparison as a more distantly related outgroup harbored only a TCRβ D1 segment with heptamers without overlapping Runx1 sites. Consistent with our model, Runx1 knockout in zebrafish, having no Runx1 binding site overlapping its TCRβ D segment heptamers, was reported to have no impact on T-cell numbers and TCRβ rearrangements 35 .…”

Section: Discussionsupporting

confidence: 87%

Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL

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Kleo

Dröge³

et al. 2020

Sci Rep

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T-cell receptor gene beta (TCRβ) gene rearrangement represents a complex, tightly regulated molecular mechanism involving excision, deletion and recombination of DNA during T-cell development. RUNX1, a well-known transcription factor for T-cell differentiation, has recently been described to act in addition as a recombinase cofactor for TCRδ gene rearrangements. In this work we employed a RUNX1 knockout mouse model and demonstrate by deep TCRβ sequencing, immunostaining and chromatin immunoprecipitation that RUNX1 binds to the initiation site of TCRβ rearrangement and its homozygous inactivation induces severe structural changes of the rearranged TCRβ gene, whereas heterozygous inactivation has almost no impact. To compare the mouse model results to the situation in Acute Lymphoblastic Leukemia (ALL) we analyzed TCRβ gene rearrangements in TALL samples harboring heterozygous Runx1 mutations. Comparable to the Runx1 +/− mouse model, heterozygous Runx1 mutations in TALL patients displayed no detectable impact on TCRβ rearrangements. Furthermore, we reanalyzed published sequence data from recurrent deletion borders of ALL patients carrying an ETV6-RUNX1 translocation. RUNX1 motifs were significantly overrepresented at the deletion ends arguing for a role of RUNX1 in the deletion mechanism. Collectively, our data imply a role of RUNX1 as recombinase cofactor for both physiological and aberrant deletions. RUNX1 belongs to the evolutionary conserved Runt transcription factor family and is indispensable for the establishment of definitive hematopoiesis in vertebrates and is an important regulator of cells of the immune system 1-3. RUNX1 is among the most frequently mutated genes in various hematological malignancies and RUNX1 alterations can lead to a loss of RUNX1 function or to a dominant-negative effect 4,5. Mono-allelic RUNX1 mutations occur in approximately 15% of T-Cell Acute Lymphoblastic Leukemia (T-ALL), predominantly in cases with an immature phenotype and a poor prognosis 6-8. In de novo Acute Myeloid Leukemia (AML) patients, somatic mutations in RUNX1 are detectable in approximately 3% of children and 15% of adults 4. In an AML subgroup with an immature phenotype (AML-M0), 30% of the cases are associated with bi-allelic inactivating RUNX1 point mutations and deletions 9. Patients with Myelodysplastic Syndrome (MDS) carrying RUNX1 mutations have a higher risk and shorter latency for progression to AML 10. Furthermore, there are over 50 different types of chromosomal translocations affecting RUNX1 4. We focus in this study on the most common translocation, t(12;21), occurring in approximately 20% of childhood B-cell

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Section: Discussionsupporting

confidence: 87%

Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL

Seitz

Kleo

Dröge³

et al. 2020

Sci Rep

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“…There are three metazoan RUNXs (RUNX1, RUNX2 and RUNX3) with different tissue-specific gene expression and functions [18]. RUNX3 plays a crucial role in definitive hematopoiesis, differentiation of T-and B-cell lineages, and neuronal development [19,20]. Recent report shows that RUNX1 may be a putative molecular target of therapies against glioma metastasis and angiogenesis that function through the activation of the p38 MAPK signaling pathway [21].…”

Section: Introductionmentioning

confidence: 99%

p38 promoted retinal micro-angiogenesis through up-regulated RUNX1 expression in diabetic retinopathy

et al. 2020

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Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and is characterized by visible microvascular alterations including retinal ischemia–reperfusion injury, inflammation, abnormal permeability, neovascularization and macular edema. Despite the available treatments, some patients present late in the course of the disease when treatment is more difficult. Hence, it is crucial that the new targets are found and utilized in the clinical therapy of DR. In the present study, we constructed a DR animal model and a model in HRMECs to investigate the relationship between p38 and RUNX1 in retinal micro-angiogenesis in diabetic retinopathy. We found that p38 could promote retinal micro-angiogenesis by up-regulating RUNX1 expression in diabetic retinopathy. This suggested that the p38/ RUNX1 pathway could become a new retinal micro-angiogenesis target in DR treatment.

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“…In hematopoiesis, RUNX1 is known to function in the formation of hematopoietic stem cells ( 12 , 31 ), the fate of macrophages/neutrophils ( 14 ), and the maturation of megakaryocytes and lymphocytes ( 19 , 32 , 33 ). Moreover, RUNX1 is one of the most frequently mutated genes in a variety of hematological malignancies, such as acute myeloid leukemia and familial platelet disorder ( 34 , 35 ).…”

Section: Discussionmentioning

confidence: 99%

Runx1 regulates zebrafish neutrophil maturation via synergistic interaction with c-Myb

Huang

Chen

Chi

et al. 2021

Journal of Biological Chemistry

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Neutrophils play an essential role in the innate immune defense system in vertebrates. During hematopoiesis, the full function of neutrophils involves maturation of granules and related enzymes. Yet, transcription regulators that promote neutrophil maturation remain largely undefined. Here, two hematopoiesis-defective zebrafish mutants, runx1 w84x and c-myb hkz3 , were used to investigate the in vivo roles of Runx1 in cooperation with c-Myb in regulating neutrophil maturation. Loss of runx1 impairs primitive neutrophil development. Additional regulation of c-myb +/− and c-myb −/− induces a more severe phenotypes suggesting a synergistic genetic interaction between c-myb and runx1 in neutrophil maturation. Further studies revealed that the two transcription factors act cooperatively to control neutrophil maturation processes via transactivating a series of neutrophil maturation-related genes. These data reveal the in vivo roles of Runx1 in regulating primitive neutrophil maturation while also indicating a novel genetic and molecular orchestration of Runx1 and c-Myb in myeloid cell development. The study will provide new evidence on the regulation of neutrophil maturation during hematopoiesis.

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Loss of runx1 function results in B cell immunodeficiency but not T cell in adult zebrafish

Cited by 14 publications

References 65 publications

Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL

Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL

p38 promoted retinal micro-angiogenesis through up-regulated RUNX1 expression in diabetic retinopathy

Runx1 regulates zebrafish neutrophil maturation via synergistic interaction with c-Myb

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