Clonal hematopoiesis-related mutant ASXL1 promotes atherosclerosis in mice via dysregulated innate immunity.

Certain somatic mutations provide a fitness advantage to hematopoietic stem cells and lead to clonal expansion of mutant blood cells, known as clonal hematopoiesis (CH). Among the most common CH mutations, ASXL1 mutations pose the highest risk for cardiovascular diseases (CVDs), yet the mechanisms by which they contribute to CVDs are unclear. Here we show that hematopoietic cells harboring C-terminally truncated ASXL1 mutant (ASXL1-MT) accelerate the development of atherosclerosis in Ldlr mice.

The E3 ligase DTX2 inhibits RUNX1 function by binding its C terminus and prevents the growth of RUNX1-dependent leukemia cells.

Transcription factor RUNX1 plays important roles in hematopoiesis and leukemogenesis. RUNX1 function is tightly controlled through posttranslational modifications, including ubiquitination and acetylation. However, its regulation via ubiquitination, especially proteasome-independent ubiquitination, is poorly understood.

IMPDH inhibition activates TLR-VCAM1 pathway and suppresses the development of MLL-fusion leukemia.

Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in de novo guanine nucleotide synthesis pathway. Although IMPDH inhibitors are widely used as effective immunosuppressants, their antitumor effects have not been proven in the clinical setting. Here, we found that acute myeloid leukemias (AMLs) with MLL-fusions are susceptible to IMPDH inhibitors in vitro.

A histone modifier, ASXL1, interacts with NONO and is involved in paraspeckle formation in hematopoietic cells.

Paraspeckles are membraneless organelles formed through liquid-liquid phase separation and consist of multiple proteins and RNAs, including NONO, SFPQ, and NEAT1. The role of paraspeckles and the component NONO in hematopoiesis remains unknown. In this study, we show histone modifier ASXL1 is involved in paraspeckle formation.

HHEX promotes myeloid transformation in cooperation with mutant ASXL1.

Additional sex combs-like 1 (ASXL1), an epigenetic modulator, is frequently mutated in myeloid neoplasms. Recent analyses of mutant ASXL1 conditional knockin (ASXL1-MT-KI) mice suggested that ASXL1-MT alone is insufficient for myeloid transformation. In our previous study, we used retrovirus-mediated insertional mutagenesis, which exhibited the susceptibility of ASXL1-MT-KI hematopoietic cells to transform into myeloid leukemia cells.

Discrimination of Dormant and Active Hematopoietic Stem Cells by G Marker Reveals Dormancy Regulation by Cytoplasmic Calcium.

Quiescent hematopoietic stem cells (HSCs) are typically dormant, and only a few quiescent HSCs are active. The relationship between "dormant" and "active" HSCs remains unresolved. Here we generate a G marker (GM) mouse line that visualizes quiescent cells and identify a small population of active HSCs (GM), which are distinct from dormant HSCs (GM), within the conventional quiescent HSC fraction.

Opposing effects of acute versus chronic inhibition of p53 on decitabine's efficacy in myeloid neoplasms.

Decitabine is a DNA methyltransferase inhibitor and is considered a promising drug to treat myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) with p53 mutations. However, whether loss of p53 in fact increases the response of MDS/AML cells to decitabine remains unclear. In this study, we assessed the role of p53 in MDS and AML cells treated with decitabine using mouse models for MLL-AF9-driven AML and mutant ASXL1-driven MDS/AML.

The ubiquitin ligase RNF38 promotes RUNX1 ubiquitination and enhances RUNX1-mediated suppression of erythroid transcription program.

RUNX1 is a member of RUNX transcription factors and plays important roles in hematopoiesis. RUNX1 function is under the tight control through posttranslational modifications, including phosphorylation and ubiquitination. We previously developed a luminescence-based binding assay (AlphaScreen) to systematically detect RUNX1-interacting E3 ubiquitin ligases.

Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis.

ASXL1 mutations occur frequently in myeloid neoplasms and are associated with poor prognosis. However, the mechanisms by which mutant ASXL1 induces leukaemogenesis remain unclear. In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis.

The ubiquitin ligase STUB1 regulates stability and activity of RUNX1 and RUNX1-RUNX1T1.

RUNX1 is a member of RUNX transcription factors and plays important roles in hematopoiesis. Disruption of RUNX1 activity has been implicated in the development of hematopoietic neoplasms. Chromosomal translocations involving the gene are associated with several types of leukemia, including acute myeloid leukemia driven by a leukemogenic fusion protein RUNX1-RUNX1T1.