Moreno Lorenzana Dafné, Juárez Velázquez María Del Rocío, Reyes León Adriana, Martínez Anaya Daniel, Hernández Monterde Adrián, Salas Labadía Consuelo, Navarrete Meneses María Del Pilar, Zapata Tarrés Marta, Juárez Villegas Luis, Jarquín Ramírez Berenice, Cárdenas Cardós Rocío, Herrera Almanza Martha, Paredes Aguilera Rogelio, Pérez Vera Patricia
Laboratorio de Genética y Cáncer, Instituto Nacional de Pediatría, Mexico City, Mexico.
Cátedra CONACYT-Instituto Nacional de Pediatría, Mexico City, Mexico.
J Pathol Clin Res. 2021 Jul;7(4):410-421. doi: 10.1002/cjp2.211. Epub 2021 Apr 23.
The gene fusions BCR-ABL1, TCF3-PBX1, and ETV6-RUNX1 are recurrent in B-cell acute lymphoblastic leukemia (B-ALL) and are found with low frequency in coexistence with CRLF2 (cytokine receptor-like factor 2) rearrangements and overexpression. There is limited information regarding the CRLF2 abnormalities and dominant-negative IKZF1 isoforms associated with surrogate markers of Jak2, ABL, and Ras signaling pathways. To assess this, we evaluated 24 Mexican children with B-ALL positive for recurrent gene fusions at diagnosis. We found CRLF2 rearrangements and/or overexpression, dominant-negative IKZF1 isoforms, and surrogate phosphorylated markers of signaling pathways coexisting with recurrent gene fusions. All the BCR-ABL1 patients expressed CRLF2 and were positive for pCrkl (ABL); most of them were also positive for pStat5 (Jak2/Stat5) and negative for pErk (Ras). TCF3-PBX1 patients with CRLF2 abnormalities were positive for pStat5, most of them were also positive for pCrkl, and two patients were also positive for pErk. One patient with ETV6-RUNX1 and intracellular CRLF2 protein expressed pCrkl. In some cases, the activated signaling pathways were reverted in vitro by specific inhibitors. We further analyzed a TCF3-PBX1 patient at relapse, identifying a clone with the recurrent gene fusion, P2RY8-CRLF2, rearrangement, and phosphorylation of the three surrogate markers that we studied. These results agree with the previous reports regarding resistance to treatment observed in patients with recurrent gene fusions and coexisting CRLF2 gene abnormalities. A marker phosphorylation signature was identified in BCR-ABL1 and TCF3-PBX1 patients. To obtain useful information for the assessment of treatment in B-ALL patients with recurrent gene fusions, we suggest that they should be evaluated at diagnosis for CRLF2 gene abnormalities and dominant-negative IKZF1 isoforms, in addition to the analyses of activation and inhibition of signaling pathways.
基因融合体BCR-ABL1、TCF3-PBX1和ETV6-RUNX1在B细胞急性淋巴细胞白血病（B-ALL）中反复出现，且在与CRLF2（细胞因子受体样因子2）重排及过表达同时存在时低频出现。关于与Jak2、ABL和Ras信号通路替代标志物相关的CRLF2异常和显性负性IKZF1亚型的信息有限。为评估此情况，我们对24名诊断时反复基因融合呈阳性的墨西哥B-ALL患儿进行了评估。我们发现CRLF2重排和/或过表达、显性负性IKZF1亚型以及与反复基因融合同时存在的信号通路替代磷酸化标志物。所有BCR-ABL1患者均表达CRLF2且pCrkl（ABL）呈阳性；其中大多数pStat5（Jak2/Stat5）也呈阳性，而pErk（Ras）呈阴性。伴有CRLF2异常的TCF3-PBX1患者pStat5呈阳性，其中大多数pCrkl也呈阳性，两名患者pErk也呈阳性。一名伴有ETV6-RUNX1和细胞内CRLF2蛋白的患者表达pCrkl。在某些情况下，活化的信号通路在体外被特异性抑制剂逆转。我们进一步分析了一名复发时的TCF3-PBX1患者，鉴定出一个具有反复基因融合、P2RY8-CRLF2重排以及我们所研究的三种替代标志物磷酸化的克隆。这些结果与先前关于反复基因融合且伴有CRLF2基因异常的患者中观察到的治疗耐药性的报道一致。在BCR-ABL1和TCF3-PBX1患者中鉴定出一种标志物磷酸化特征。为获取对伴有反复基因融合的B-ALL患者治疗评估有用的信息，我们建议除了分析信号通路的激活和抑制外，还应对他们在诊断时进行CRLF2基因异常和显性负性IKZF1亚型的评估。
