Integrin-α9 overexpression underlies the niche-independent maintenance of leukemia stem cells in acute myeloid leukemia.

Leukemia stem cells (LSCs) are widely believed to reside in well-characterized bone marrow (BM) niches; however, the capacity of the BM niches to accommodate LSCs is insufficient, and a significant proportion of LSCs are instead maintained in regions outside the BM. The molecular basis for this niche-independent behavior of LSCs remains elusive. Here, we show that integrin-α9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with its soluble ligand, osteopontin (OPN).

Mitochondria transfer mediates stress erythropoiesis by altering the bioenergetic profiles of early erythroblasts through CD47.

Intercellular mitochondria transfer is a biological phenomenon implicated in diverse biological processes. However, the physiological role of this phenomenon remains understudied between erythroblasts and their erythroblastic island (EBI) macrophage niche. To gain further insights into the mitochondria transfer functions, we infused EBI macrophages in vivo into mice subjected to different modes of anemic stresses.

Loss of METTL3 attenuates blastic plasmacytoid dendritic cell neoplasm response to PRMT5 inhibition via IFN signaling.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with poor clinical outcomes. Dysregulated MYC expression, which is associated with protein arginine methyltransferase 5 (PRMT5) dependency, is a recurrent feature of BPDCN. Although recent studies have reported a PRMT5 gene signature in BPDCN patient samples, the role of PRMT5 in BPDCN remains unexplored.

Myeloma cells self-promote migration by regulating TAB1-driven TIMP-1 expression in mesenchymal stem cells.

Multiple myeloma (MM) is an intractable hematological malignancy characterized by abnormal plasma cells in the bone marrow (BM) and increased osteolytic lesions. Within the BM niche, mesenchymal stem cells (MSCs) have been proposed to contribute to functionally important MM-MSC interactions. However, despite various studies on MM pathology, the impact of MM on MSCs during the early stages of malignancy has not been adequately addressed.

Hematopoietic stem cells acquire survival advantage by loss of RUNX1 methylation identified in familial leukemia.

RUNX1 is among the most frequently mutated genes in human leukemia, and the loss or dominant-negative suppression of RUNX1 function is found in myelodysplastic syndrome and acute myeloid leukemia (AML). How posttranslational modifications (PTMs) of RUNX1 affect its in vivo function, however, and whether PTM dysregulation of RUNX1 can cause leukemia are largely unknown. We performed targeted deep sequencing on a family with 3 occurrences of AML and identified a novel RUNX1 mutation, R237K.

PRMT5 Modulates Splicing for Genome Integrity and Preserves Proteostasis of Hematopoietic Stem Cells.

Protein arginine methyltransferase 5 (PRMT5) is essential for hematopoiesis, while PRMT5 inhibition remains a promising therapeutic strategy against various cancers. Here, we demonstrate that hematopoietic stem cell (HSC) quiescence and viability are severely perturbed upon PRMT5 depletion, which also increases HSC size, PI3K/AKT/mechanistic target of rapamycin (mTOR) pathway activity, and protein synthesis rate. We uncover a critical role for PRMT5 in maintaining HSC genomic integrity by modulating splicing of genes involved in DNA repair.

Sphingosine-1-phosphate signaling modulates terminal erythroid differentiation through the regulation of mitophagy.

Erythropoiesis is a highly coordinated stepwise process involving the progressive clearance of mitochondria via mitophagy. Based on the expression of several macroautophagy and mitophagy specific genes, we identified a sequential change in the transcriptional pattern during terminal erythroid differentiation. Because erythroid cells are a major source of serum sphingosine-1-phosphate, we analyzed the role of sphingolipid signaling in erythropoiesis and demonstrate that sphingosine kinase activity promotes terminal erythroid differentiation by regulating the expression of key mitophagy genes Pink1 and Bnip3l/Nix.

Macrophage response to oncolytic paramyxoviruses potentiates virus-mediated tumor cell killing.

Tumor-associated macrophages (TAMs) are known to regulate tumor response to many anti-cancer therapies, including oncolytic virotherapy. Oncolytic virotherapy employing oncolytic paramyxoviruses, such as attenuated measles (MeV) and mumps (MuV) viruses, has demonstrated therapeutic potential against various malignancies. However, the response of TAMs to oncolytic paramyxoviruses and the consequent effect on virotherapeutic efficacy remains to be characterized.