CDKN2B downregulation and other genetic characteristics in T-acute lymphoblastic leukemia

Abstract

We identified principal genetic alterations in 97.1% (99/102) of patients with T-acute lymphoblastic leukemia (T-ALL) using integrative genetic analyses, including massive parallel sequencing and multiplex ligation-dependent probe amplification (MLPA). A total of 133 mutations were identified in the following genes in descending order: NOTCH1 (66.7%), FBXW7 (19.6%), PHF6 (15.7%), RUNX1 (12.7%), NRAS (10.8%), and DNMT3A (9.8%). Copy number alterations were most frequently detected in CDKN2B, CDKN2A, and genes on 9p21.3 in T-ALL (45.1%). Gene expression data demonstrated the downregulation of CDKN2B in most cases of T-ALL, whereas CDKN2A downregulation was mainly restricted to deletions. Additional quantitative methylation analysis demonstrated that CDKN2B downregulation stemmed from deletion and hypermethylation. Analysis of 64 patients with CDKN2B hypermethylation indicated an association with an older age of onset and early T cell precursor ALL, which involved very early arrest of T cell differentiation. Genes associated with methylation and myeloid neoplasms, including DNMT3A and NRAS, were more commonly mutated in T-ALL with CDKN2B hypermethylation. In particular, a CDKN2B biallelic deletion or high methylation level (≥45%), the age of onset, and the GATA3 and SH2B3 mutations were factors associated with a poor prognosis. This study clarifies that one of the most important genetic events in T-ALL, namely, CDKN2B downregulation, occurs mechanistically via deletion and hypermethylation. Different susceptible genetic backgrounds exist based on the CDKN2B downregulation mechanism.

Pharmacological properties and therapeutic potential of saffron (Crocus sativus L.) in osteosarcoma

“…Except CDKN2B, no marked variation was detected in the expression of selected genes as a result of saffron in osteosarcoma cells. CDKN2B is a cyclin‐dependent kinase inhibitor which makes complex with CDK4 or CDK6 and interferes with the activation of cyclin‐dependent kinases . Importantly, expression of CDKN2B was shown to be diminished or lost in multiple types of human cancers, suggesting its significant tumour suppressor role .…”

“…CDKN2B is a cyclin-dependent kinase inhibitor which makes complex with CDK4 or CDK6 and interferes with the activation of cyclin-dependent kinases. [23] Importantly, expression of CDKN2B was shown to be diminished or lost in multiple types of human cancers, suggesting its significant tumour suppressor role. [23,24] Taken together our findings suggest that both dichloromethane and hexane extracts of saffron target the expression of tumour suppressor CDKN2B gene in osteosarcoma cells to show antitumour effects.…”

“…[23] Importantly, expression of CDKN2B was shown to be diminished or lost in multiple types of human cancers, suggesting its significant tumour suppressor role. [23,24] Taken together our findings suggest that both dichloromethane and hexane extracts of saffron target the expression of tumour suppressor CDKN2B gene in osteosarcoma cells to show antitumour effects. Additionally, we also established the DNA laddering which is a significant event used for the analysis of cells undergoing apoptosis.…”

Drug Resistance Biomarkers and Their Clinical Applications in Childhood Acute Lymphoblastic Leukemia

“…Deletion of the 9p21 chromosomal region leads to deletion in these proteins, controlling G1/S cell-cycle progression, and are identified in 21-36% of pediatric B-ALL (consisting of 42 children and 60 adults) (31). Furthermore, CDKN2A deletion is also correlated with poor event-free survival (EFS) in pediatric T-ALL (39).…”

Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

“…The SH2B3 protein specifically binds to phosphorylated tyrosine and acts as a central negative regulatory node for multiple signaling pathways [86,129]. Loss-of-function mutations in SH2B3 are reported to play an important role in the oncogenesis of myeloproliferative neoplasms (MPN), early T-ALL, Ph-like ALL, B-ALL and nonmalignant hematological diseases by accelerating STAT3 phosphorylation and increased NOTCH-1 signaling [130][131][132][133]. Thus, SH2B3 can attenuate IL7-stimulated JAK/STAT5 signaling.…”