RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils

Zezulin, Alexandra U.; Ye, Darwin; Howell, Elizabeth D.; Yen, Daniel; Bresciani, Erica; Diemer, Jamie; Ren, Jian‐Gang; Ahmad, Mohd Hafiz; Castilla, Lucio H.; Touw, Ivo P.; Minn, Andy J.; Tong, Wei; Liu, P. Paul; Tan, Kai; Yu, Wenboa; Speck, Nancy A.

doi:10.1101/2023.01.27.525911

Cited by 2 publications

(1 citation statement)

References 68 publications

(79 reference statements)

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“…IFITMs are important effectors in innate immunity and cancer biology 44,45 and RUNX1 is a negative regulator of neutrophil cytokine production 56,57 . The IFITM3 upregulation in RUNX1 -deficient HEL cells and MK (Figures 6 and 7) is novel and maybe relevant to autoimmune manifestations 12,58 and leukemic predisposition of FPDMM.…”

Section: Discussionmentioning

confidence: 99%

Altered Platelet-Megakaryocyte Endocytosis and Trafficking of Albumin and Fibrinogen inRUNX1Haplodeficiency

Carpio-Cano,

Mao,

Goldfinger

et al. 2023

Preprint

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Platelet α-granules have numerous proteins, some synthesized by megakaryocytes (MK) and others not synthesized but incorporated by endocytosis, an incompletely understood process in platelets/MK. Germline RUNX1 haplodeficiency, referred to as familial platelet defect with predisposition to myeloid malignancies (FPDMM), is associated with thrombocytopenia, platelet dysfunction and granule deficiencies. In previous studies, we found that platelet albumin, fibrinogen and IgG levels were decreased in a FPDMM patient. We now show that platelet endocytosis of fluorescent-labeled albumin, fibrinogen and IgG is decreased in the patient and his daughter with FPDMM. In megakaryocytic human erythroleukemia (HEL) cells, siRNA RUNX1 knockdown (KD) increased uptake of these proteins over 24 hours compared to control cells, with increases in caveolin-1 and flotillin-1 (two independent regulators of clathrin-independent endocytosis), LAMP2 (a lysosomal marker), RAB11 (a marker of recycling endosomes) and IFITM3. Caveolin-1 downregulation in RUNX1-deficient HEL cells abrogated the increased uptake of albumin, but not fibrinogen. Albumin, but not fibrinogen, partially colocalized with caveolin-1. RUNX1 knockdown increased colocalization of albumin with flotillin and of fibrinogen with RAB11 suggesting altered trafficking of both. The increased albumin and fibrinogen uptake and levels of caveolin-1, flotillin-1, LAMP2 and IFITM3 were recapitulated by shRNA RUNX1 knockdown in CD34+-derived MK. These studies provide the first evidence that in RUNX1-haplodeficiency platelet endocytosis of albumin and fibrinogen is impaired and that megakaryocytes have enhanced endocytosis with defective trafficking leading to loss of these proteins by distinct mechanisms. They provide new insights into mechanisms governing endocytosis and α-granule deficiencies in RUNX1-haplodeficiency.

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Section: Discussionmentioning

confidence: 99%

Altered Platelet-Megakaryocyte Endocytosis and Trafficking of Albumin and Fibrinogen inRUNX1Haplodeficiency

Carpio-Cano,

Mao,

Goldfinger

et al. 2023

Preprint

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RUN(X) out of blood: emerging RUNX1 functions beyond hematopoiesis and links to Down syndrome

Rozen,

Ozeroff,

Allen

2023

Hum Genomics

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Background RUNX1 is a transcription factor and a master regulator for the specification of the hematopoietic lineage during embryogenesis and postnatal megakaryopoiesis. Mutations and rearrangements on RUNX1 are key drivers of hematological malignancies. In humans, this gene is localized to the ‘Down syndrome critical region’ of chromosome 21, triplication of which is necessary and sufficient for most phenotypes that characterize Trisomy 21. Main body Individuals with Down syndrome show a higher predisposition to leukemias. Hence, RUNX1 overexpression was initially proposed as a critical player on Down syndrome-associated leukemogenesis. Less is known about the functions of RUNX1 in other tissues and organs, although growing reports show important implications in development or homeostasis of neural tissues, muscle, heart, bone, ovary, or the endothelium, among others. Even less is understood about the consequences on these tissues of RUNX1 gene dosage alterations in the context of Down syndrome. In this review, we summarize the current knowledge on RUNX1 activities outside blood/leukemia, while suggesting for the first time their potential relation to specific Trisomy 21 co-occurring conditions. Conclusion Our concise review on the emerging RUNX1 roles in different tissues outside the hematopoietic context provides a number of well-funded hypotheses that will open new research avenues toward a better understanding of RUNX1-mediated transcription in health and disease, contributing to novel potential diagnostic and therapeutic strategies for Down syndrome-associated conditions.

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RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils

Cited by 2 publications

References 68 publications

Altered Platelet-Megakaryocyte Endocytosis and Trafficking of Albumin and Fibrinogen inRUNX1Haplodeficiency

Altered Platelet-Megakaryocyte Endocytosis and Trafficking of Albumin and Fibrinogen inRUNX1Haplodeficiency

RUN(X) out of blood: emerging RUNX1 functions beyond hematopoiesis and links to Down syndrome

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