The prognostic significance of cytokine receptor-like factor 2 expression and JAK2 mutation in pediatric B-cell acute lymphoblastic leukemia: A prospective cohort study

Abstract

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Philadelphia (Ph)-like B-cell acute lymphoblastic leukemia (B-ALL) is defined by a gene expression profile similar to Phpositive B-ALL and shows a large number of genetic alterations in the cytokine receptor and kinasesignaling pathway genes that contribute to its aggressive phenotype and frequent disease recurrence – the main cause of death in affected children. Here, we aimed to correlate CRLF2 expression and JAK2 mutations in B-ALL patients with other prognostic factors and the patients’ outcomes as well as to evaluate their prognostic significance. The study was approved by the local institutional review board and written consents were obtained from a parent of each child before their enrolment. We included 54 newly diagnosed B-ALL pediatric patients (median age: 9.0 (2.0–18.0)) who were stratified either into a standard-risk (SR) or high-risk (HR) group and treated according to the modified BerlinFrankfurt-Münster 90 protocol (ALL-BFM 90). Fresh bone marrow samples were used to determine CRLF2 expression as well as to search for the JAK2 V617F mutation. Normal CRLF2 expression was reported in the SR patients much more often than in the HR group, while its overexpression was more common in the HR patients than in the SR ones (22 vs 6 and 18 vs 8, respectively, p < 0.001). CRLF2 was also more often overexpressed in the MRD-positive cases than in the negative ones (17 vs 9, p < 0.001), while normal CRLF2 expression was more common in the MRD-negative patients compared to the MRD-positive ones (24 vs 4, p < 0.001) which supports the unfavorable prognostic value of CRLF2 in relation to MRD positivity at the end of the induction treatment. JAK2 mutation was detected only in 2 patients belonging to the CRLF2 overexpression group which made the assessment of the prognostic significance of this mutation impossible. Notably, none of the patients with normal CRLF2 expression ended up relapsing while 4 patients with overexpressed CRLF2 developed a relapse (p = 0.031). The study subjects were followed up for up to 24 months, and we did not find CRLF2 overexpression to negatively influence overall survival, however, it did have an adverse effect on relapse-free survival. In summary, CRLF2 overexpression was found to be an unfavorable prognostic factor in childhood ALL as it was expressed more in high-risk patients and in those with poor treatment response. The analysis of CRLF2 expression in B-ALL pediatric patients may help in risk stratification and can potentially offer new treatment options based on novel CRLF2 inhibitors.