Department of Urology & Pathology, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
Cancer. 2024 Mar 1;130(5):713-726. doi: 10.1002/cncr.35051. Epub 2023 Oct 11.
Philadelphia chromosome (Ph)-like B-acute lymphoblastic leukemia (B-ALL) is a clinically significant, high-risk genetic subtype of B-ALL cases. There are few data on the incidence, characterization, and treatment outcomes of Ph-like ALL cases from low- and middle-income countries. There is a pressing need to establish a well-organized/cost-effective approach for identifying Ph-like ALL instances.
Multiplex reverse transcriptase polymerase chain reaction, nCounter NanoString, and fluorescence in situ hybridization were used to detect and characterize Ph-like ALL cases among recurrent genetic abnormalities (RGA) B-ALL cases. At the end of induction therapy, flow cytometry-minimal residual disease (MRD) assay was used to quantify MRD positivity in Ph-like ALL cases.
Of 130 newly diagnosed B-ALL cases, 25% (BCR::ABL1), 4% (ETV6::RUNX1), 5% (TCF3::PBX1), 2% (KM2TA::AFF1), and 65% RGA B-ALL cases were revealed by multiplex reverse transcriptase polymerase chain reaction. Among RGA B-ALL cases, 24% Ph-like ALL cases using nCounter NanoString were identified, with 48% CRLF2 cases with 45% CRLF2::P2RY8 and 18% CRLF2::IGH rearrangements(∼r) revealed by fluorescence in situ hybridization. In 52% of CRLF2 cases, 17% ABL1 and JAK2∼r 8% EPOR::IGH & PDGRFB∼r were identified. Ph-like ALL cases had higher total leukocyte count (p < .05), male preponderance (p < .05), and high MRD-positivity/induction failure compared with RGA B-ALL cases. Furthermore, in Ph-like ALL cases, 11 significant genes using quantitative polymerase chain reaction were identified and validated. CRLF2, IGJ, CEACAM6, MUC4, SPATS2L and NRXN3 genes were overexpressed and show statistical significance (p < .05) in Ph-like ALL cases.
This study showed the high incidence of Ph-like ALL cases with kinase activating alterations and treatment outcomes from low- and middle-income region. Furthermore, a surrogate cost-effective multiplex panel of 11 overexpressed genes for the prompt detection of Ph-like ALL cases is proposed.
Identification of recurrent gene abnormalities (RGA) B-acute lymphoblastic leukemia (B-ALL) cases using multiplex-reverse transcriptase polymerase chain reaction. Identification and characterization of Philadelphia (Ph)-like ALL cases using nCounter NanoString gene expression profiling and fluorescence in situ hybridization. Furthermore, Ph-like ALL cases were characterized according to CRLF2 expression and kinase-activating genomic alterations. Minimal residual disease of Ph-like ALL cases were quantified using flow cytometry-minimal residual disease assay. A surrogate molecular approach was established to detect Ph-like ALL cases from low- and middle-income countries.
费城染色体（Ph）样 B 急性淋巴细胞白血病（B-ALL）是一种临床上重要的、高风险的 B-ALL 遗传亚型。来自中低收入国家的 Ph 样 ALL 病例的发病率、特征和治疗结果的数据很少。迫切需要建立一种组织良好/具有成本效益的方法来识别 Ph 样 ALL 病例。
采用多重逆转录酶聚合酶链反应、nCounter NanoString 和荧光原位杂交技术检测和分析复发性遗传异常（RGA）B-ALL 病例中的 Ph 样 ALL 病例。在诱导治疗结束时，采用流式细胞术-微小残留病（MRD）检测方法定量 Ph 样 ALL 病例的 MRD 阳性率。
在 130 例新诊断的 B-ALL 病例中，25%（BCR::ABL1）、4%（ETV6::RUNX1）、5%（TCF3::PBX1）、2%（KM2TA::AFF1）和 65% RGA B-ALL 病例通过多重逆转录酶聚合酶链反应检测到。在 RGA B-ALL 病例中，使用 nCounter NanoString 鉴定出 24%的 Ph 样 ALL 病例，其中 48%的 CRLF2 病例存在 45%的 CRLF2::P2RY8 和 18%的 CRLF2::IGH 重排（∼r）通过荧光原位杂交检测到。在 52%的 CRLF2 病例中，鉴定出 17%的 ABL1 和 JAK2∼r 和 8%的 EPOR::IGH & PDGRFB∼r。Ph 样 ALL 病例的总白细胞计数较高（p<0.05），男性居多（p<0.05），MRD 阳性率/诱导失败率高于 RGA B-ALL 病例。此外，在 Ph 样 ALL 病例中，通过定量聚合酶链反应鉴定并验证了 11 个重要基因。CRLF2、IGJ、CEACAM6、MUC4、SPATS2L 和 NRXN3 基因在 Ph 样 ALL 病例中过表达，并具有统计学意义（p<0.05）。
本研究显示了中低收入地区 Ph 样 ALL 病例的高发生率及激酶激活改变和治疗结果。此外，提出了一种具有成本效益的 11 个过表达基因的替代多重检测方法，用于快速检测 Ph 样 ALL 病例。
