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The prognosis for adult B-cell acute lymphoblastic leukemia remains unfavorable, especially in the context of relapsed and refractory disease. Exploring the molecular mechanisms underlying disease progression holds significant promise for improving clinical outcomes. In this investigation, utilizing single-cell transcriptome sequencing technology, we discerned a correlation between Ubiquitin-like containing PHD and RING finger domain 1 (UHRF1) and the progression of B-cell acute lymphoblastic leukemia. Our findings reveal a significant upregulation of UHRF1 in cases of relapsed and refractory B-cell acute lymphoblastic leukemia, thereby serving as a prognostic indicator for poor outcomes. Both deletion of UHRF1 or overexpression of its downstream target secreted frizzled-related protein 5 (SFRP5) resulted in the inhibition of leukemia cell proliferation, promoting cellular apoptosis and induction of cell cycle arrest. Our results showed that UHRF1 employs methylation modifications to repress the expression of SFRP5, consequently inducing the WNT5A-P38 MAPK-HK2 signaling axis, resulting in the augmentation of lactate, the critical metabolic product of aerobic glycolysis. Furthermore, we identified UM164 as a targeted inhibitor of UHRF1 that substantially inhibits P38 protein phosphorylation, downregulates HK2 expression, and reduces lactate production. UM164 also demonstrated antileukemic activity both in vitro and in vivo. In summary, our investigation revealed the molecular mechanisms of epigenetic and metabolic reprogramming in relapsed and refractory B-cell acute lymphoblastic leukemia and provides potential targeted therapeutic strategies to improve its inadequate prognosis. The schematic model showed the regulator network of UHRF1-SFRP5-WNT5A-P38 MAPK-HK2 in B-ALL.

B cell acute lymphoblastic leukemia (B-ALL) blasts hijack the bone marrow (BM) microenvironment to form chemoprotective leukemic BM niches facilitating chemoresistance and, ultimately, disease relapse. However, the ability to dissect these evolving, heterogeneous interactions among distinct B-ALL subtypes and their varying BM niches is limited with current in vivo methods. Here, we demonstrated an in vitro organotypic leukemia-on-a-chip" model to emulate the in vivo B-ALL BM pathology and comparatively studied the spatial and genetic heterogeneity of the BM niche in regulating B-ALL chemotherapy resistance. We revealed the heterogeneous chemoresistance mechanisms across various B-ALL cell lines and patient-derived samples. We showed that the leukemic perivascular endosteal and hematopoietic niche-derived factors maintain B-ALL survival and quiescence (e.g. CXCL12 cytokine signal VCAM-1/OPN adhesive signals and enhanced downstream leukemia-intrinsic NF-$\kappa$B pathway). Furthermore we demonstrated the preclinical use of our model to test niche-cotargeting regimens which may translate to patient-specific therapy screening and response prediction."

Scleroderma (SSc) is an autoimmune connective tissue disease characterized by immune dysregulation, vasculopathy, and fibrosis. We have previously demonstrated that low Fli1 expression in SSc fibroblasts and endothelial cells plays an important role in SSc pathogenesis. Cells of myeloid and lymphoid origin also express Fli1 and are dysregulated in patients with SSc, playing key roles in disease pathogenesis. However, the role for immune Fli1 in SSc is not yet clear. Our aim was to elucidate whether Fli1 contributes to the immune dysregulation seen in SSc. Comparison of the expression of Fli1 in monocytes, B- and T-cell fractions of PBMCs isolated from SSc patients and healthy controls (HC), showed an increase in Fli1 levels in monocytes. We used siRNA transfected human myeloid cells and mouse peritoneal macrophages obtained from Fli1 flox/flox LysMCre+/+ mice, and found that markers of alternative macrophage activation were increased with Fli1 deletion. Coculture of Fli1-deficient myeloid cells and primary human or mouse fibroblasts resulted in a potent induction of collagen type I, independent of TGF$\beta$ upregulation. We next analyzed global gene expression profile in response to Fli1 downregulation, to gain further insight into the molecular mechanisms of this process and to identify differentially expressed genes in myeloid cells. Of relevance to SSc, the top most upregulated pathways were hallmark IFN-$\gamma$ and IFN-$\alpha$ response. Additionally, several genes previously linked to SSc pathogenesis and fibrosis in general were also induced, including CCL2, CCL7, MMP12, and CXCL10. ANKRD1, a profibrotic transcription co-regulator was the top upregulated gene in our array. Our results show that Fli1-deficient myeloid cells share key features with cells from SSc patients, with higher expression of profibrotic markers and activation of interferon responsive genes, thus suggesting that dysregulation of Fli1 in myeloid cells may contribute to SSc pathogenesis.