title: The Role of Histone Protein Modifications and Mutations in Histone Modifiers in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia.
abstract: While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes includeMLL1,CREBBP,NSD2, andSETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis.
authors.affiliation: Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz 91-738, Poland. szymon.janczar@umed.lodz.pl.
authors.forename: Szymon
authors.initials: S
authors.lastname: Janczar
authors.affiliation: Department of Pathology, Medical University of Lodz, Lodz 92-213, Poland. karolina.janczar@umed.lodz.pl.
authors.forename: Karolina
authors.initials: K
authors.lastname: Janczar
authors.affiliation: Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz 91-738, Poland. agata.pastorczak@umed.lodz.pl.
authors.forename: Agata
authors.initials: A
authors.lastname: Pastorczak
authors.affiliation: Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, Marburg 35043, Germany. harbh@staff.uni-marburg.de.
authors.forename: Hani
authors.initials: H
authors.lastname: Harb
authors.affiliation: Department of Life Sciences, University of Bedfordshire, Bedfordshire LU1 3JU, UK. Adam.Paige@beds.ac.uk.
authors.forename: Adam J W
authors.initials: AJ
authors.lastname: Paige
authors.affiliation: Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz 91-738, Poland. beata.zalewska-szewczyk@umed.lodz.pl.
authors.forename: Beata
authors.initials: B
authors.lastname: Zalewska-Szewczyk
authors.affiliation: Department of Pathology, Medical University of Lodz, Lodz 92-213, Poland. marian.danilewicz@umed.lodz.pl.
authors.forename: Marian
authors.initials: M
authors.lastname: Danilewicz
authors.affiliation: Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz 91-738, Poland. wojciech.mlynarski@umed.lodz.pl.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Mlynarski
keywords: B lymphocytes; acute lymphoblastic leukemia; chromatin modifiers; histone modifications