مقالات پذیرفته شده در ششمین کنگره بین المللی زیست پزشکی
Genomic landscape of chronic lymphocytic leukemia
Genomic landscape of chronic lymphocytic leukemia
Behdokht Fathi Dizaji,1,*
1. Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Introduction: Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm, defines as accumulation of apparently normal, mature CD5+, CD10 - , CD19+, CD20+, and CD23+ lymphocytes in the peripheral blood, bone marrow and lymphoid tissues. CLL accounts for 40% of adult leukemias, almost 70 years at diagnosis, and 1F:2M sex ratio. Family history is observed in 5–10% of CLL patients or other non-Hodgkin lymphoma which is the highest genetic susceptibility among hematologic neoplasms.
Methods: This study is a review of the genetic basis of Chronic lymphocytic leukemia, through assessing related articles using databases, ScienceDirect, PubMed and GoogleScholar.
Results: Cytogenetic: nearly 80% of patients have a recurrent chromosomal abnormality mainly, del (13q14.3), del (11q22.1)/ ATM, del (17p13.1)/ TP53), del (6q23.3)/ MYB, and +12. 50-60% of CLL patients have13q14 deletion that is the most common genetic defect. large deletions engage RB1gene with poor prognosis. Other recurrent copy number alternations also were reported: 1p, 1q23.2q23.3, 2p12p25.3, 3p21.31, 3q, 4p15.2p16.3, 6p25.3, 6p22.1, 6q, 7p, 7q, 8p21, 8q24.1, 9q13q21.11, 10q24, 11q22.3, 12, 14q24.1q32.3, 14q32 deletion, 15q15.1, 17q, 18p, and19. 14q24.1q32.33 deletion have been observer in 48% of patients. +2p is a recurrent abnormality in heterogeneous CLL populations. large scale studies identified chromothripsis in 4–5% of patients.
Translocations, especially ones that not involve IGH, are rare in CLL. The t(14;19) (q32;q13) IGH/BCL3 is a recurrent translocation mostly found with trisomy 12. t(14;18)(q32;q21) results in IGH/BCL2 fusion . t(18;22)(q21;q11.2) BCL2/IGL and t(2;18)(p12;q21) IGK/BCL2 are observed as secondary aberrations in patients. Rarely MYC [t(8;14)(q24.1;q32) IGH/MYC t(2;8)(p12;q24.1) IGK/MYC and t(8;22)(q24.1;q11.2) MYC/IGL can be observed in CLL. translocations in 13q14 and 17p13 are unbalanced and deletions in the breakpoints were detected. Recently, a rare patient with trisomy 12 and t (14;18) was described.
Considering the mutations of the IGHV gene (variable region of the immunoglobulin heavy chain) patients are classified in two molecular subtypes. mutated IGHV patients present an indolent CLL while, unmutated IGHV patients exhibit an aggressive form of CLL.
Genome-wide association studies (GWAs) have recognized approximately 45 susceptibility loci for CLL mostly mapping to noncoding regions.
Using next generation sequencing, 11 recurrent somatic copy number changes and 44 recurrent mutations in genes comprising, ATM, SF3B1, NOTCH1, TP53, MYD88, DDX3X, CHD2, HIST1C1 (chromatin regulators), XPO1, RANBP2 (RNA export factors), RAS, MAP2K1, MAP2K3 (signal transducers), EGR2, IKZF3 (B-cell transcription factors), RPS15 (ribosomal proteins) and POT1 (telomere-associated proteins) were recognized. Down-regulation of PAX5 was shown via mutations of an enhancer found on 9p13.
TP53, ATM, IGHV mutations and complex karyotype have an intensive poor prognosis.
epigenetic profiling, exhibited differential DNA methylation between CLLs and controls. higher epigenetic heterogeneity observed in more aggressive CLL subgroups. Few epigenetic changes can be attributed as exactly CLL-specific alternations. Therefore, CLL patients classified in three epigenetic subgroups with a distinct clinical consequence: naive B-cell like, intermediate and memory B-cell like, With different IGHV mutational state.
Non-coding RNAs
13q14 deletion includes LncRNA DLEU2, miR15-a/miR16-1 genes. These two microRNAs are essential in maintaining the balance of apoptosis of B lymphocytes. Besides, an alternative transcript in this locus raises cell cycle progression through cyclin D1 and angiotensin I converting enzyme 2. Other microRNAs involving in CLL encompass: miR-27b, miR-29a-c, miR-125b, miR-146a, miR-155, miR-202-3p, miR-150, miR-499, miR-574, miR-106a, and miR-9. As an example, miR-202-3p Promotes CLL progression and can be considered as a therapeutic target.
High level of circRNA mc-COX2 is associated with CLL progression and prognosis.
Various snoRNAs were recognized as potential biomarkers via assessment of the snoRNAs expression in CLL patients. SNORD116-23, SNORD116-29, SNORA36A SNORD94, SNORD116-1 were down-regulated in CLL. In patients, the SNORA31expression is associated with the expression of its host gene, (TPT1), which is a target of TP53.
Conclusion: CLL is heterogeneous clinically and genetically. Genetic analysis provides the basis of diagnosis, prognosis and treatment choices for the disease. Whole genome analysis revealed new CLL genomic drivers and molecular pathways that has encouraged scientists to fulfill new prognostic classifications and therapeutic targets. The major challenge in this area is how to apply our knowledge into clinical practice.