Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia

Newly diagnosed acute lymphoblastic leukemia in China (I): abnormal genetic patterns in 1346 childhood and adult cases and their comparison with the reports from Western countries

“…14,15 Interestingly, CRLF2 overexpression and IKZF1 splicing deletion, which are significantly more involved in adults than in children, are both related to the poor outcome in B-ALL and closely associated with JAK mutations. 16,18,45 Analyzed by gene expression profiling, the three abnormal transcriptional signatures of CRLF2 overexpression, IKZF1 aberration and BCR --ABL demonstrated a high degree of similarity, suggesting the presence of similar pathogenic mechanisms with interference of the transcriptional regulations or signaling pathways that control the proliferation, survival and self-renewal of hematopoietic stem cells. 18,45 In parallel, we observed that MLL gene was more frequently involved in adults than in children, supporting the point of view that epigenetic regulatory pathway, which has an important role in the pathogenesis of leukemia may contribute more to the onset of adult ALL than to that of in pediatric ones.…”

“…16,18,45 Analyzed by gene expression profiling, the three abnormal transcriptional signatures of CRLF2 overexpression, IKZF1 aberration and BCR --ABL demonstrated a high degree of similarity, suggesting the presence of similar pathogenic mechanisms with interference of the transcriptional regulations or signaling pathways that control the proliferation, survival and self-renewal of hematopoietic stem cells. 18,45 In parallel, we observed that MLL gene was more frequently involved in adults than in children, supporting the point of view that epigenetic regulatory pathway, which has an important role in the pathogenesis of leukemia may contribute more to the onset of adult ALL than to that of in pediatric ones. 46 --48 On the basis of these data, we conclude that the cytogenetic/molecular abnormalities in the pathogenesis of pediatric and adult ALL might be substantially different.…”

“…The cut-off value of CRLF2 overexpression was identified according to Yoda et al 15 Genomic rearrangement was confirmed by fluorescence in situ hybridization for the detection of breakpoints of IGH@ locus (LSI IGH@ Dual Color Break-Apart Rearrangement Probe, Abbott Diagnostics, Chicago, IL, USA) and involvement of CRLF2 on chromosome X, 16 and genomic PCR for the PAR1 deletion resulting in fusion of P2RY8 --CRLF2 transcript, which was also confirmed by RT-PCR. 17,18 (Supplementary Figure 2).…”

Genomic profiling of high-risk acute lymphoblastic leukemia

“…P2RY8 is a member of a family of purinergic receptor genes that is expressed in hematopoietic cells, including leukemic blasts, and has previously been identified as a rare target of translocation to SOX5 in lymphoma. 72 CRLF2 alterations in B-progenitor ALL have been subsequently confirmed and identified by multiple groups, including adult ALL 61,70,71,73,74 (Table 1). CRLF2 is rearranged in five to seven percent of B-progenitor childhood ALL cases, most commonly by IGH@-CRLF2 rearrangement or the PAR1 deletion resulting in expression of P2RY8-CRLF2.…”

“…These alterations were adjacent to the CRLF2 locus at PAR1, and were associated with markedly elevated expression of CRLF2. 70 Notably, Russell, Harrison and colleagues had also identified dysregulated expression of CRLF2 arising from rearrangement of CRLF2 into the immunoglobulin heavy chain locus (IGH@-CRLF2), or associated with the PAR1 deletion, in a subset of B-progenitor ALL. 71 Defining the precise limits of the PAR1 deletion was difficult due to poor microarray probe coverage of the PAR1 region, but mapping using high resolution microarrays and long range genomic PCR showed that the deletion extended from intron 1 of P2RY8 (encoding the purinergic receptor gene P2Y, G-protein coupled, 8) to immediately upstream of the first coding exon of CRLF2.…”