Morphological, immunophenotypic, and genetic features of chronic lymphocytic leukemia with trisomy 12: a comprehensive review

Abstract

Chronic lymphocytic leukemia is an extremely heterogeneous disease and prognostic factors such as chromosomal abnormalities are important predictors of time to first treatment and survival. Trisomy 12 is the second most frequent aberration detected by fluorescence in situ hybridization at the time of diagnosis (10–25%), and it confers an intermediate prognostic risk, with a median time to first treatment of 33 months and a median overall survival of 114 months. Here, we review the unique morphological, immunophenotypic, and genetic characteristics of patients with chronic lymphocytic leukemia and trisomy 12. These patients carry a significantly higher expression of CD19, CD22, CD20, CD79b, CD24, CD27, CD38, CD49d, sIgM, sIgk, and sIgλ and lower expression of CD43 compared with patients with normal karyotype. Circulating cells show increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and of the adhesion molecule CD323. Patients with chronic lymphocytic leukemia and trisomy 12 frequently have unmutated IGHV, ZAP-70 positivity, and closely homologous stereotyped B-cell receptors. They rarely show TP53 mutations but frequently have NOTCH1 mutations, which can be identified in up to 40% of those with a rapidly progressive clinical course.

Cold agglutinin–associated B-cell lymphoproliferative disease shows highly recurrent gains of chromosome 3 and 12 or 18

“…Trisomy 12 is frequent in patients with small lymphocytic lymphoma (28%-36%) and chronic lymphocytic leukemia (10%-25%), and in the latter 112 is associated with intermediate prognosis. 19,20 Trisomy 3 and 18 are found to be correlated with advanced-stage extranodal MZL. 17 There is evidence from previous studies that trisomy 18 may be associated with upregulation of BCL2, an antiapoptotic gene located on chromosome 18.…”

Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors

“…The accumulation of malignant cells in CLL appears to be driven by both intrinsic genetic alterations and a tumor-promoting effect of the microenvironment [ 1 , 13 ]. The most common chromosomal changes include deletion of part of chromosome 13q (resulting in overexpression of the anti-apoptotic BCL2 protein due to loss of repressing miRNAs within this chromosomal region), deletions of 17p or 11q (which result in defective DNA damage responses due to loss of genes encoding p53 or ATM) or trisomy 12 (the functional consequences of which are not well understood) [ 14 – 16 ]. In addition, next generation sequencing has identified recurrent somatic mutations, the most common of which are loss-of-function mutations of p53 or ATM, activating mutations of NOTCH1 (which leads to enhanced NOTCH1 signaling) and mutations of SF3B1 (which encodes a splicing factor) and XPO1 (which encodes a protein involved in nuclear export of proteins and RNAs) [ 17 , 18 ].…”

Prognosis and new therapeutic approaches in chronic lymphocytic leukemia treatment

“…Dener (Döhner) i sar. su okarakterisali trizomiju 12q kao marker intermedijarne prognoze (kraće OS u odnosu na HLL bolesnike sa del13q) (8,9). Delecija kratkog kraka hromozoma 17 (del17p) pojavljuje se kod oko 5-8% bolesnika obolelih od HLL koji nisu lečeni, ali se prevalencija ove abnormalnosti povećava čak do 30% tokom evolucije bolesti (1,3,10).…”

“…Otašević V. et al Prognoza i savremeno lečenje bolesnika sa hroničnom limfocitnom leukemijom. MedPodml 2019, 70(4): [6][7][8][9][10][11][12] Hronična limfocitna leukemija (HLL) najčešća je leukemija u zapadnim zemljama, čineći 30% leukemija u Evropi i Sjedinjenim Američkim Državama. Ujedno predstavlja jedno od najaktivnijih polja u hematologiji po pitanju kliničkih istraživanja.…”