An overall characterization of pediatric acute lymphoblastic leukemia with CRLF2 overexpression

Abstract

For an overall characterization of pediatric B-cell precursor acute lymphoblastic leukemia (BCPALL) with CRLF2 overexpression (OE), we conducted genetic analysis of CRLF2 in 167 pediatric BCPALL patients. CRLF2 OE was detected in 30 (18%) of 167 patients, the P2RY8-CRLF2 fusion was identified in only 3 (1.8%) of 167 patients, all of which demonstrated CRLF2 OE. Moreover, CRLF2 gain was identified in 18 (11%) of 167 patients. Messenger RNA sequencing revealed a novel fusion transcript, CSF2RA-CRLF2, in a case with CRLF2 OE, suggesting that this fusion is associated with CRLF2 OE. In survival analysis, no significant differences in 5-year event-free survival (EFS) and overall survival were observed between patients with and without CRLF2 OE (70.7 vs. 75.4%, log rank P = 0.68 and 96.4 vs. 82.1%, log rank P = 0.11, respectively). However, a significant difference in 5-year EFS between CRLF2 OE patients with and without IKZF1 deletion was observed (44.4 vs. 83.1%, log rank P = 0.02). In multivariate analysis, only IKZF1 deletion was a significant predictor of inferior OS (hazard ratio: 2.427, P = 0.04).These findings suggest that CRLF2 OE is not an independent prognostic factor in pediatric BCPALL.

Prognostic significance of P2RY8‐CRLF2 and CRLF2 overexpression may vary across risk subgroups of childhood B‐cell acute lymphoblastic leukemia

“…Among the risk subgroups, the HR subgroup showed the biggest difference in prevalence of an extra copy of sex chromosome (40.0% vs. 6.2%, P = 0.007). Similar observations have been reported by others (Chen et al, ; Yano et al, ). This supports the notion that CRLF2 overexpression is attributed to an acquiring additional copy of CRLF2 on the X or Y chromosome.…”

“…Various frequencies of CRLF2 overexpression have been reported in the literature. U.S. Children's Oncology Group and a study of Japanese pediatric B‐ALL series observed CRLF2 overexpression in 17–18% of unselected B‐ALL cases (Chen et al, ; Yano et al, ). Harvey et al reported CRLF2 overexpression in 14% of patients with HR B‐ALL (Harvey et al, ).…”

HighCRLF2expression associates withIKZF1dysfunction in adult acute lymphoblastic leukemia withoutCRLF2rearrangement

“…CRLF2 rearrangement occurs at high frequency in Down Syndrome ALL [3, 9, 19] and in patients of Hispanic/Latino ethnicity [21]. However the rate of CRLF2 overexpression occurs at a higher frequency in patients than CRLF2 rearrangement [9, 22]. Thus CRLF2 rearrangement is unable fully to explain the mechanisms underlying CRLF2 overexpression in ALL patients.…”

The role of G protein-coupled receptors in lymphoid malignancies

“…Fusion of the purinergic receptor P2RY8 promoter to the CRLF2 (cytokine receptor like factor 2) gene frequently occurs in B-ALL but reports of the functional consequences of this rearrangement have been conflicting. Although P2RY8-CRLF2 fusions were significantly correlated with poor outcome in adolescent and adult patients [15, 16], the consequences of the fusion in pediatric B-ALL is less clear as some studies have found it to be associated with poor outcome [17–19] whereas others have not found any significant correlation [20, 21]. A meta-analysis of these studies concluded that presence of the P2RY8-CRLF2 fusion was in fact significantly associated with poor prognosis of relapse-free survival and event-free survival [22].…”

“…A meta-analysis of these studies concluded that presence of the P2RY8-CRLF2 fusion was in fact significantly associated with poor prognosis of relapse-free survival and event-free survival [22]. Another finding among these studies was that P2RY8-CRLF2 was more common in B-ALL patients with trisomy 21 [19, 23–26] or intrachromosomal amplification of chromosome 21 [27] than those with normal chromosome 21 [1, 18–21, 25, 26, 28–30]. …”