title: Morphoproteomics Identifies SIRT1 and EZH2 Pathways as Commonalities in B-cell Acute Lymphoblastic Leukemia: Pathogenetic Implications and Opportunities for Therapeutic Intervention.
abstract: B-cell acute lymphoblastic leukemia (ALL) represents a malignant process in which bone marrow-derived lymphoblasts retain their undifferentiated state. Genetic testing has revealed either no identifiable cytogenetic and genomic abnormalities in such patients or a wide range of aberrations that may or may not contribute to the block in differentiation and the associated proliferation of the malignant lymphoblasts in cases of B-cell ALL. In this study, we applied morphoproteomics to a representative spectrum of cases of newly diagnosed B-cell ALL in order to identify pathways that are known to be associated with the maintenance of the undifferentiated state while promoting proliferation. Our results showed nuclear expression in a majority of the lymphoblasts from bone marrow clot preparations of each of the study cases for both silent mating type information regulation 2 homolog 1 (SIRT1), an NAD+ histone deacetylase and enhancer of Zeste homolog 2 (EZH2), a histone methyltransferase. These represent pathogenetic pathways capable of blocking differentiation and promoting proliferation of the B-cell ALL lymphoblasts. Data mining of the National Library of Medicine's MEDLINE Database and Ingenuity Pathway analysis revealed agents of relatively low toxicity-melatonin, metformin, curcumin and sulforaphane-that are capable of inhibiting directly or pharmacogenomically one or both of the SIRT1 and EZH2 pathways and should, in a combinatorial fashion, remove the block in differentiation and decrease the proliferation of the B-cell ALL lymphoblasts.
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth, McGovern Medical School, Houston, Texas, USA Robert.Brown@uth.tmc.edu.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Brown
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Konopka
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth, McGovern Medical School, Houston, Texas, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Weerasinghe
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth, McGovern Medical School, Houston, Texas, USA.
authors.forename: Vanya
authors.initials: V
authors.lastname: Jaitly
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth, McGovern Medical School, Houston, Texas, USA.
authors.forename: Amitava
authors.initials: A
authors.lastname: Dasgupta
authors.affiliation: Biomedical Analytics, Houston, Texas, USA.
authors.forename: Mary F
authors.initials: MF
authors.lastname: McGuire
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth, McGovern Medical School, Houston, Texas, USA.
authors.forename: Nghia D
authors.initials: ND
authors.lastname: Nguyen
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000071221:Enhancer of Zeste Homolog 2 Protein; D056564:Sirtuin 1
keywords: B-cell ALL; EZH2; SIRT1; morphoproteomics