Novakova Michaela, Zaliova Marketa, Fiser Karel, Vakrmanova Barbora, Slamova Lucie, Musilova Alena, Brüggemann Monika, Ritgen Matthias, Fronkova Eva, Kalina Tomas, Stary Jan, Winkowska Lucie, Svec Peter, Kolenova Alexandra, Stuchly Jan, Zuna Jan, Trka Jan, Hrusak Ondrej, Mejstrikova Ester
CLIP-Dpt.of Paediatric Haematology/Oncology, Charles University, Prague, Czech Republic.
Dpt.of Paediatric Haematology/Oncology, University Hospital Motol, Charles University, Czech Rep.
Haematologica. 2021 Aug 1;106(8):2066-2075. doi: 10.3324/haematol.2020.250423.
Recently, we described B-cell precursor acute lymphoblastic leukemia (BCP-ALL) subtype with early switch to the monocytic lineage and loss of the B-cell immunophenotype, including CD19 expression. Thus far, the genetic background has remained unknown. Among 726 children consecutively diagnosed with BCP-ALL, 8% patients experienced switch detectable by flow cytometry (FC). Using exome and RNA sequencing, switch was found to positively correlate with three different genetic subtypes: PAX5-P80R mutation (5 cases with switch out of 5), rearranged DUX4 (DUX4r; 30 cases of 41) and rearranged ZNF384 (ZNF384r; 4 cases of 10). Expression profiles or phenotypic patterns correlated with genotypes, but within each genotype they could not identify cases who subsequently switched. If switching was not taken into account, the B-cell-oriented FC assessment underestimated the minimal residual disease level. For patients with PAX5-P80R, a discordance between FC-determined and PCR-determined MRD was found on day 15, resulting from a rapid loss of the B-cell phenotype. Discordance on day 33 was observed in all the DUX4r, PAX5-P80R and ZNF384r subtypes. Importantly, despite the substantial phenotypic changes, possibly even challenging the appropriateness of BCP-ALL therapy, the monocytic switch was not associated with a higher incidence of relapse and poorer prognosis in patients undergoing standard ALL treatment.
最近，我们描述了一种B细胞前体急性淋巴细胞白血病（BCP-ALL）亚型，其会早期转换为单核细胞谱系并丧失B细胞免疫表型，包括CD19表达。迄今为止，其遗传背景仍不清楚。在连续诊断为BCP-ALL的726名儿童中，8%的患者出现了可通过流式细胞术（FC）检测到的转换。通过外显子组和RNA测序发现，转换与三种不同的遗传亚型呈正相关：PAX5-P80R突变（5例转换者中有5例）、重排的DUX4（DUX4r；41例中有30例）和重排的ZNF384（ZNF384r；10例中有4例）。表达谱或表型模式与基因型相关，但在每种基因型中，它们无法识别随后发生转换的病例。如果不考虑转换情况，以B细胞为导向的FC评估会低估微小残留病水平。对于携带PAX5-P80R的患者，在第15天发现FC测定的和PCR测定的MRD之间存在不一致，这是由于B细胞表型的快速丧失所致。在所有DUX4r、PAX5-P80R和ZNF384r亚型中，在第33天均观察到不一致情况。重要的是，尽管有显著的表型变化，甚至可能对BCP-ALL治疗的适宜性提出挑战，但单核细胞转换与接受标准ALL治疗的患者更高的复发率和更差的预后无关。
