Abstract
Simple SummaryB-ALL is the more frequent childhood malignancy. Even though significant improvements in patients’ survival, some pediatric B-ALL have still poor prognosis and novel strategies are needed. Recently, new genetic abnormalities and altered signaling pathways have been described, defining novel B-ALL subtypes.Innovative targeted therapeutic drugs may potentially show a great impact on the treatment of B-ALL subtypes, offering an important chance to block multiple signaling pathways and potentially improving the clinical management of B-ALL younger patients, especially for the new identified subtypes that lack efficient chemotherapeutic protocols. In this review, we shed light on the up-to-date knowledge of the novel childhood B-ALL subtypes and the altered signaling pathways that could become new druggable targets.B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy that arises from the clonal expansion of transformed B-cell precursors and predominately affects childhood. Even though significant progresses have been made in the treatment of B-ALL, pediatric patients’ outcome has to be furtherly increased and alternative targeted treatment strategies are required for younger patients. Over the last decade, novel approaches have been used to understand the genomic landscape and the complexity of the molecular biology of pediatric B-ALL, mainly next generation sequencing, offering important insights into new B-ALL subtypes, altered pathways, and therapeutic targets that may lead to improved risk stratification and treatments. Here, we will highlight the up-to-date knowledge of the novel B-ALL subtypes in childhood, with particular emphasis on altered signaling pathways. In addition, we will discuss the targeted therapies that showed promising results for the treatment of the different B-ALL subtypes.
Highlights
B-cell acute lymphoblastic leukemia (B-ALL) is a group of blood malignancies that results from the clonal expansion of transformed B-cell precursors, representing around 25% of all pediatric tumors and more than 80% of pediatric ALL [1]
PAX5 rearrangements may occur with different partners, such as POM121, BRD1, DACH1, HIPK1 and JAK2 (PAX5-JAK2 rearrangement has been found in Philadelphia Chromosome-like (Ph-like) ALL, leading to aberrant activation of Janus kinase (JAK)/signal transducer and activator of transcription proteins (STAT) signaling pathway) and all these rearrangements are observed in approximately 11% of B-ALL childhood patients [73]
Further frequent alterations have been found in PAX5alt patients and involve different genes, including CDKN2A, IKZF1, ETV6 and LEF1, or lead to epigenetic modifications in KDM6A, KMT2A or Through induced PAX5 loss, Liu et al, reported that PAX5 deficiency contributes to leukemogenesis, by supporting B-ALL self-renewal and by blocking a differentiation program that can be re-engaged despite the presence of additional oncogenic lesions to B-ALL maintenance [74]
Summary
Stefano Ratti 1,† , Annalisa Lonetti 2,† , Matilde Y. Martelli 1 , Francesca Chiarini 3,4, * and Camilla Evangelisti 3,4, *. CNR Institute of Molecular Genetics Luigi Luca Cavalli-Sforza, Via di Barbiano 1/10, 40136 Bologna, Italy. New genetic abnormalities and altered signaling pathways have been described, defining novel B-ALL subtypes.Innovative targeted therapeutic drugs may potentially show a great impact on the treatment of B-ALL subtypes, offering an important chance to block multiple signaling pathways and potentially improving the clinical management of B-ALL younger patients, especially for the new identified subtypes that lack efficient chemotherapeutic protocols. We shed light on the up-to-date knowledge of the novel childhood B-ALL subtypes and the altered signaling pathways that could become new druggable targets
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