The enigmatic role(s) of P2RY8-CRLF2

CRLF2, the gene encoding the cytokine receptorlike factor 2, is located in the pseudoautosomal region 1 (PAR1) of both sex chromosomes. Its aberrant expression is the defining feature of an otherwise genetically heterogeneous relapse-prone group of B cell precursor acute lymphoblastic leukemias (BCP ALL) in children and adolescents. The two most common causative genetic defects are, first, an interstitial deletion that juxtaposes the first noncoding exon of P2RY8 to the entire CRLF2 coding region and, second, a chromosomal translocation that places CRLF2 under the control of the IGH enhancer [1]. IGH-CRLF2 fusions occur in a hematopoietic stem/ progenitor cell and are considered initiating events while P2RY8-CRLF2 fusions are caused by illegitimate V(D) J-mediated recombination and therefore only occur in a B precursor cell. Both CRLF2 fusions often carry additional alterations in CRLF2/IL7R/JAK-STAT pathway genes and may cooperatively activate downstream pathways. Interestingly, basically all IGH-CRLF2 fusions belong to the Ph-like group of B-other ALL while only a smaller proportion of those with a P2RY8-CRLF2 fusion do [2]. Considering these facts and additional differences in the ethnic background, age, sex, WBC and outcome of patients affected by the one or other fusion, it appears likely that these two fusions define distinct disease entities. They have a particular association with chromosome 21 alterations, either in the form of constitutional trisomy (half of all Down syndrome ALL have such a fusion) or, albeit exclusively for P2RY8-CRLF2, in the form of a somatically acquired primary or secondary alteration. Although P2RY8-CRLF2 itself is a well-recognized risk indicator for relapse, its specific biological relevance for disease recurrence is still unclear and therefore a matter of ongoing discussion. Outcome data from different study groups are difficult to compare and interpret, because analyzed cohorts, patient numbers, observation periods and treatment regimens differ, as do screening techniques and ascertainment algorithms. To clarify these issues in a systematic way, we evaluated the salient features of P2RY8-CRLF2-positive leukemias by quantifying their clone sizes at diagnosis and relapse and correlated them with the respective CRLF2 expression levels. These analyses revealed that the majority of P2RY8-CRLF2positive clones are small at diagnosis and virtually never evolve into dominant relapse clones. These findings therefore prove that neither the presence of this alteration nor CRLF2 overexpression alone provide the affected clones with any noteworthy proliferative or selective advantage [3]. As mentioned before, P2RY8-CRLF2 often evolves as a secondary alteration in leukemias with preexisting, usually primary changes such as a iAMP21, hyperdiploidy and dic(9;20). They concur with other deletions mainly affecting B cell differentiation, cell cycle control and tumor suppression. With the exception of P2RY8-CRLF2, these genetic alterations are generally conserved in the dominant relapse clone. To analyze the way in which these clones differ, we studied the mutation and expression patterns at diagnosis and relapse with whole exome and Editorial