Development Of B-cell Acute Lymphoblastic Leukemia Research Articles

Endothelial-derived small extracellular vesicles support B-cell acute lymphoblastic leukemia development.

The bone marrow niche plays an important role in leukemia development. However, the contributions of different niche components to leukemia development and their underlying mechanisms remain largely unclear. Cre/LoxP-based conditional knockout technology was used to delete VPS33B or ANGPTL2 gene in niche cells. Murine B-ALL model was established by overexpressing the N-Myc oncogene in hematopoietic stem progenitor cells. The frequency of leukemia cells and immunophenotypic B220+ CD43+ LICs was detected by flow cytometry. SEVs was isolated by sequential centrifugation and mass spectrometry was performed to analyze the different components of SEVs. Immunoprecipitation and western blot were used to measure the interaction of VPS33B and ANGPTL2. Here, we showed that specific knockout of vascular protein sorting 33b (Vps33b) in endothelial cells (ECs), but not megakaryocytes or mesenchymal stem cells, resulted in a significant decrease in the secretion of small extracellular vesicles (SEVs) and a delay in the development of B-cell lymphoblastic leukemia (B-ALL). Vps33b knockdown endothelial cells contained much lower levels of SEVs that contained angiopoietin-like protein 2 (ANGPTL2) than the control cells. Importantly, conditional knockout of Angptl2 in ECs significantly delayed B-ALL progression. Moreover, C-terminal region of ANGPTL2 (aa247-471) could directly interact with Sec1-like domain 1 of VPS33B (aa1-aa146). We further demonstrated that the point mutations R399H and G402S in ANGPTL2 led to a dramatic decrease in the secretion of ANGPTL2-SEVs. We also showed that wild-type ANGPTL2-containing SEVs, but not mutant ANGPTL2-containing SEVs, significantly enhanced B-ALL development. In summary, our findings indicate that the secretion of ANGPTL2-containing SEVs in ECs sustains the leukemogenic activities of B-ALL cells, which is fine-tuned by the direct interaction of VPS33B and ANGPTL2. These findings reveal that niche-specific SEVs play an important role in B-ALL development.

EP300-ZNF384 Rearrangement Drive B-Cell Acute Lymphoblastic Leukemia Development By Activating IL3-IL3RA Signaling

Abstract: EP300-ZNF384 chromosome rearrangement serves as an oncogenic driver in B-cell acute lymphoblastic leukemia development. However, the oncogenic mechanisms underlying EP300-ZNF384 remain largely elusive. Recent evidence shows that the gene expression signature in EP300-ZNF384-positive patients enriched in cytokine-cytokine receptor and JAK-STAT signaling. We reason the correlated cytokine-cytokine receptor and JAK-STAT signaling might play important roles in EP300-ZNF384 fusion primed B-cell acute lymphoblastic leukemia. To investigate this concept, we identified EP300-ZNF384 substantially induces the expression of IL3RA on cell membranes of B lineage cells. Further, we proved IL3 supplement promotes EP300-ZNF348 positive cells proliferation and colony formation by activating JAK-STAT signaling. IL3RA knockdown reduces the responsiveness of EP300-ZF384 positive cells to IL3 stimulation. Dual luciferase assay and ChIP-qPCR assay confirm that EP300-ZNF384 binds the promoter region of IL3RA and actives its transcription. Interestingly, IL3 expression was significantly upregulated in ZNF384 rearranged B-cell acute lymphoblastic leukemia patients comparing with B others through analyzing bioinformatics databases. These findings underscore the critical role of IL3-IL3RA signaling under EP300-ZNF384 driven B-cell acute lymphoblastic leukemia and imply EP300-ZNF384 positive patients might benefit from JAK inhibitors. Keywords: EP300-ZNF384, B-cell Acute Lymphoblastic leukemia, IL3RA, IL3 JAK, STAT

Amerindian genetic ancestry and INDEL polymorphisms associated with susceptibility of childhood B-cell Leukemia in an admixed population from the Brazilian Amazon

Acute lymphoblastic leukemia (ALL) is a malignant tumor common in children. Studies of genetic susceptibility to cancer using biallelic insertion/deletion (INDEL) type polymorphisms associated with cancer development pathways may help to clarify etymology of ALL. In this study, we investigate the role of eight functional INDEL polymorphisms and influence of genetic ancestry to B-cell ALL susceptibility in children of Brazilian Amazon population, which has a high degree of inter-ethnic admixture. Ancestry analysis was estimated using a panel of 48 autosomal ancestry informative markers. 130 B-cell ALL patients and 125 healthy controls were included in this study. The odds ratios and 95% confidence intervals were adjusted for confounders. The results indicated an association between the investigated INDEL polymorphisms in CASP8 (rs3834129), CYP19A1 (rs11575899) e XRCC1 (rs3213239) genes in the development of B-cell ALL. The carriers of Insertion/Insertion (Ins/Ins) genotype of the polymorphism in CASP8 gene presented reduced chances of developing B-cell ALL (P=0.001; OR=0.353; 95% CI=0.192–0.651). The Deletion/Deletion (Del/Del) genotype of the polymorphism in CYP19A1 gene was associated to a lower chance of developing B-cell ALL (P=3.35×10−6; OR=0.121; 95% CI=0.050–0.295), while Del/Del genotype of the polymorphism in XRCC1 gene was associated to a higher chance of developing B-cell ALL (P=2.01×10−4; OR=6.559; 95% CI=2.433–17.681). We also found that Amerindian ancestry correlates with the risk of B-cell ALL. For each increase of 10% in the Amerindian ancestry results in 1.4-fold chances of developing B-cell ALL (OR=1.406; 95% IC=1.123–1.761), while each increase of 10% in the European ancestry presents a protection effect in the development of B-cell ALL (OR=0.666; 95% IC=0.536–0.827). The results suggest that genetic factors influence leukemogenesis and might be explored in the stratification of B-cell ALL risk in admixed populations.