Leukemia, Chronic Lymphocytic, Susceptibility To, 5

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Retrieved

2019-09-22

Source

OMIM

Trials

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Genes

POT1, CCND1, TP53, ATM, ARL11, P2RX7, IKZF3, IGHV3-21, IGHG1, RPS15, BCL2, LEF1, DLEU1, IRF4, CFLAR, FARP2, BCL2L11, TSBP1-AS1, FAS, TSBP1, NCAPH2, RREB1, ELL2, QPCT, PRKD2, PCAT1, IPCEF1, DACT3-AS1, C11orf21, SP140, ACOXL-AS1, FAM126B, ULK4, MDS2, LRRC34, DRAIC, CIB3, GGNBP1, BMF, VMP1, CLPTM1L, RFX7, ILRUN, CSRNP1, RHOU, GRAMD1B, RPS6KB1, ACOXL, BANK1, MIR4435-2HG, MYNN, ACTA2, CASC19, SERPINB6, IRF8, SP110, HLA-DQA1, HDLBP, GPR37, PVT1, DTNB, LPP, MGAT5, HLA-DQA2, OAS3, OPRM1, NCK1, CASP10, CASP8, BAK1, HLA-DRB1, SLC35B2, PIK3CD, BTK, MS4A1, LOC102724971, LOC102723407, SELL, KRT20, NOTCH1, CD40LG, IBTK, CD5, IKZF2, CCR8, ETS1, PWWP3A, ETS2, CDKN1B, CD22, CD79A, BTLA, MIR34B, MIR155, RAD51, IFNGR2, PIK3CA, PIK3CG, CCL13, SKP2, TNF, PIM1, TRAF2, CDR3, PIK3CB, KALRN, SLC28A1, CIB1, IGH, RAD51AP1, MME, KMT2A, LTB, IGHV3OR16-7, IGHV3-69-1, ITGAX, ITGA4, IL13, IL7R, IL12A

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For a phenotypic description and discussion of genetic heterogeneity of chronic lymphocytic leukemia (CLL), see 151400.

Mapping

Di Bernardo et al. (2008) conducted a genomewide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia and performed validation in 2 additional series totaling 1,529 cases and 3,115 controls. They identified 6 previously unreported CLL risk alleles, the second strongest of which was rs735665, which maps to a 131-kb region of linkage disequilibrium at chromosome 11q24.1. The combined odds ratio for this SNP was 1.45, 95% confidence interval of 1.31 to 1.61 and a P value of 3.78 x 10(-12). The only gene detected in the region was GRAMD1B, approximately 50 kb telomeric to rs735665. This gene is expressed in lymphoid tissue.

In a 3-stage genomewide association study to identify susceptibility loci for non-Hodgkin lymphoma subtypes, Conde et al. (2010) confirmed the previously reported association between CLL/small lymphocytic lymphoma and rs735665 (combined p = 4.24 x 10(-9)).

Pathogenesis

Fabbri et al. (2011) found that CLL cells with a chromosome 11q23 deletion had significantly lower expression levels of MIRN34B (611374) and MIRN34C (611375) and significantly higher expression levels of ZAP70 (176947) than CLL cells with normal cytogenetic profiles. Patients with these changes had poorer overall survival compared to those without these changes. A binding site for the MIRN34 family was detected in the ZAP70 open reading frame and reduced ZAP70 expression was observed in primary B-CLL cells from a patient with a chromosome 11q+/- deletion, in which MIRN34A (611172), MIRN34B, and MIRN34C were overexpressed. TP53 (191170) directly stimulated the transcription of the miRNAs, and the miRNAs in turn directly targeted and inhibited ZAP70. Involvement of TP53 with MIRN15A (609703) and MIRN16-1 (609704) in a feedback loop was also observed in CLL cells with a chromosome 13q14 deletion (109543). Moreover, changes in 1 family of miRNAs indirectly affected the expression of another miRNA family by modulating the levels of TP53. Fabbri et al. (2011) concluded that their findings indicated that a microRNA/TP53 feedback circuitry is associated with the pathogenesis and prognosis of CLL.