Co-Detection of VEGF-A and Its Regulator, microRNA-181a, May Indicate Central Nervous System Involvement in Pediatric Leukemia

Abstract

Central nervous system (CNS) involvement is a leading cause of therapy-refractory pediatric acute lymphoblastic leukemia (pALL), which is aggravated by underdiagnosing CNS disease with the currently used cell-based approach of cerebrospinal fluid (CSF) diagnostics. Our study focused on developing novel subcellular CNS leukemia indicators in the CSF and the bone marrow (BM) of patients with pALL. Serial liquid biopsy samples (n = 65) were analyzed by Elisas to measure the level of essential proteins associated with blast cell CNS trafficking, vascular endothelial growth factor A (VEGF-A) and integrin alpha 6 (ITGA6). In CSF samples from early induction chemotherapy, VEGF-A concentration were uniformly elevated in the CNS-positive group compared to those patients without unambiguous meningeal infiltration (9 vs Nine patients, Δc = 17.2 pg/ml, p = 0.016). Expression of miR-181a, a VEGFA-regulating microRNA which showed increased level in CNS leukemia in our previous experiments, was then paralleled with VEGF-A concentration. A slight correlation between the levels of miR-181a and VEGF-A indicators in CSF and BM samples was revealed (n = 46, Pearson’s r = 0.36, p = 0.015). After validating in international cohorts, the joint quantification of miR-181a and VEGF-A might provide a novel tool to precisely diagnose CNS involvement and adjust CNS-directed therapy in pALL.

An Interpretable Machine Learning Framework for Rare Disease: A Case Study to Stratify Infection Risk in Pediatric Leukemia

“…Evidence from ALL trials with hematopoietic growth factors is mixed; some studies suggest a reduction in severe infections by myeloid growth factors, whereas others report no effect [ 71 ]. Growth factors, like VEGF-A, have also been tied to CNS invasion in pediatric leukemia [ 72 ].…”

“…Central nervous system infiltration has long been considered an important factor in describing potential pediatric leukemia prognoses. Recent work found that the co-detection of the growth factor VEGF-A and microRNA-181a may indicate central nervous system involvement in pediatric leukemia [ 72 ]. Finally, there is a plethora of evidence that shows older age, namely >10 years of age at diagnosis, to be associated with more negative outcomes in pediatric acute leukemias [ 77 ].…”

A Comprehensive Overview of Recent Advances in Epigenetics in Pediatric Acute Lymphoblastic Leukemia

“…For this reason, inhibition of miR-181a-5p can be used as a therapeutic strategy for the treatment of ALL [ 67 ]. Moreover, in research by Egyed B et al carried out on various ALL genetic subgroups as normal karyotype, hyperdiploid, high hyperdiploid, KMT2A-rearranged, P2RY8-CRLF2 translocated, CDKN2A deleted and ETV6 deleted, the level of miR-181a or miR-181a in combination with Vascular endothelial growth factor A (VEGF-A) detected in the cerebrospinal fluid can be useful in the future as a marker of central nervous system (CNS) involvement in pediatric ALL [ 68 , 69 ]. A study by El-Khazragy N et al found that a high level of miR-181a and miR-155 in bone marrow cells was correlated with a higher risk of recurrence and poor response to treatment.…”