RT Journal Article
T1 High BMP4 expression in low/intermediate risk BCP-ALL identifies children with poor outcomes
A1 Martínez Fernández De Sevilla, Lidia
A1 Valencia Mahón, Jaris
A1 Ortiz Sánchez, Paula
A1 Fraile Ramos, Alberto
A1 Zuluaga Arias, María del Pilar
A1 Jiménez Pérez, Eva
A1 Sacedón Ayuso, Rosa
A1 Vicente López, María Ángeles
A1 Varas Fajardo, Alberto
AB Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) outcome has improved in the last decades, but leukemic relapses are still one of the main problems of thisdisease. Bone morphogenetic protein 4 (BMP4) was investigated as a new candidate biomarker with potential prognostic relevance, and its pathogenic role was assessed in the development of disease. A retrospective study was performed with 115 pediatric patients with BCP-ALL, and BMP4 expression was analyzed by quantitative reverse transcription polymerase chain reaction in leukemic blasts at the time of diagnosis. BMP4 mRNA expression levels in the third (upper) quartile were associated with a higher cumulative incidence of relapse as well as a worse 5-year event-free survival and central nervous system (CNS) involvement. Importantly, this association was also evident among children classified as having a nonhigh risk of relapse. A validation cohort of 236 patients with BCP-ALL supported these data. Furthermore, high BMP4 expression promoted engraftment and rapid disease progression in an NSG mouse xenograft model with CNS involvement. Pharmacological blockade of the canonical BMP signaling pathway significantly decreased CNS infiltration and consistently resulted in amelioration of clinical parameters, including neurological score. Mechanistically, BMP4 favored chemoresistance, enhanced adhesion and migration through brain vascular endothelial cells, and promoted a proinflammatory microenvironment and CNS angiogenesis. These data provide evidence that BMP4 expression levels in leukemic cells could be a useful biomarker to identify children with poor outcomes in the low-/intermediate-risk groups of BCP-ALL and that BMP4 could be a new therapeutic target to blockade leukemic CNS disease.
SN 0006-4971
SN 1528-0020
YR 2022
FD 2022-06-02
LK https://hdl.handle.net/20.500.14352/114456
UL https://hdl.handle.net/20.500.14352/114456
LA eng
NO Fernández-Sevilla LM, Valencia J, Ortiz-Sánchez P, Fraile-Ramos A, Zuluaga P, Jiménez E, Sacedón R, Martínez-Sánchez MV, Jazbec J, Debeljak M, Fedders B, Stanulla M, Schewe DM, Cario G, Minguela A, Ramírez M, Varas A, Vicente Á. High BMP4 expression in low/intermediate risk BCP-ALL identifies children with poor outcome. Blood. 2022 (2 Junio 2022 | Volume 139, number 22 pp. 3303-13/ doi: 10.1182/blood.2021013506)
NO Spanish Ministry of Economy and Competitiveness
NO Institute of Health Carlos III, Spain
NO Community of Madrid
NO Uno Entre Cien Mil Foundation
DS Docta Complutense
RD 7 abr 2025