Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - RNA-seq

B-cell prolymphocytic leukemia (B-PLL) is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.EGA study EGAS00001003274

B细胞幼淋巴细胞白血病（B-cell prolymphocytic leukemia, B-PLL）是一种罕见疾病，其分子病理机制迄今尚未完全阐明。本研究对34例B-PLL患者组成的大样本队列的细胞遗传学与分子生物学特征进行了报道。73%的患者核型存在复杂异常（≥3种染色体畸变），45%的患者核型为高度复杂核型（HCK≥5）。最常见的染色体畸变包括：靶向MYC基因的染色体易位[t(MYC)]（62%）、累及TP53基因的17p染色体缺失（38%）、18号染色体三体/18q三体（30%）、13q14区域缺失（29%）、3号染色体三体（24%）、12号染色体三体（24%）以及8p染色体缺失（23%）。对16例患者开展的全外显子组测序结果显示，TP53（6/16，38%）、MYD88（n=4）、BCOR（n=4）、MYC（n=3）、SF3B1（n=3）、FAT1（n=3）、SETD2（n=2）、CHD2（n=2）、CXCR4（n=2）及BCLAF1（n=2）存在复发性突变。其中21例（62%）患者携带t(MYC)，该亚组患者的幼淋巴细胞比例更高（p=0.03）、CD38表达阳性率更高（p<0.001）、核型复杂程度更低（p=0.0004），且伴随MYC突变以及参与RNA代谢与染色质重塑的基因突变。基因表达谱数据的主成分分析显示，携带t(MYC)的患者可聚为独立聚类簇。另一亚组包含5例（15%）存在MYC基因扩增的患者，该亚组与HCK≥5（p=0.01）及3号染色体三体（p=0.008）显著相关。整体而言，34例患者中26例（76%）存在MYC激活（易位或扩增），且这类MYC异常彼此互斥。本研究鉴定出3个独立的细胞遗传学预后分组（p=0.0006）：低危组（无MYC激活，中位生存期未达到）、中危组（存在MYC激活但无17p缺失，中位生存期125个月）以及高危组（存在MYC激活且伴随17p缺失，中位生存期11个月）。本研究结果表明，细胞遗传学分析可作为B-PLL有效的诊断工具，有助于优化患者的预后分层。本研究隶属于EGA研究项目EGAS00001003274