Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group

Abstract

We report gene expression and other analyses to elucidate the molecular characteristics of acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS). We find that by gene expression DS-ALL is a highly heterogeneous disease not definable as a unique entity. Nevertheless, 62% (33/53) of the DS-ALL samples analyzed were characterized by high expression of the type I cytokine receptor CRLF2 caused by either immunoglobulin heavy locus (IgH@) translocations or by interstitial deletions creating chimeric transcripts P2RY8-CRLF2. In 3 of these 33 patients, a novel activating somatic mutation, F232C in CRLF2, was identified. Consistent with our previous research, mutations in R683 of JAK2 were identified in 10 specimens (19% of the patients) and, interestingly, all 10 had high CRLF2 expression. Cytokine receptor-like factor 2 (CRLF2) and mutated Janus kinase 2 (Jak2) cooperated in conferring cytokine-independent growth to BaF3 pro-B cells. Intriguingly, the gene expression signature of DS-ALL is enriched with DNA damage and BCL6 responsive genes, suggesting the possibility of B-cell lymphocytic genomic instability. Thus, DS confers increased risk for genetically highly diverse ALLs with frequent overexpression of CRLF2, associated with activating mutations in the receptor itself or in JAK2. Our data also suggest that the majority of DS children with ALL may benefit from therapy blocking the CRLF2/JAK2 pathways. (Blood.

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.…”

“…Less commonly, CRLF2 is rearranged to other, as yet unknown partner genes or harbors presumed activating mutations, most commonly F232C. 73,75 A striking observation is that CRLF2 alteration, most commonly the PAR1 deletion, is present in over 50% of ALL associated with Down's syndrome (DS-ALL), 61,74 in which other chromosomal rearrangements characteristic of childhood ALL are uncommon. 76 The basis for this increased frequency in DS-ALL is currently unknown.…”

“…61 Before the identification of CRLF2 alterations in ALL, JAK mutations in ALL were shown (like the JAK2 V617F mutation observed in myeloproliferative disease) to transform Ba/F3 cells expressing the erythropoietin receptor (Ba/F3-EpoR cells) to cytokineindependent growth and result in constitutive Jak-Stat activation, 56,63,66 suggesting that interaction of Jak mutants with a cytokine receptor scaffold is required for transformation. Subsequent studies have shown that coexpression of JAK mutations and CRLF2 in Ba/F3 cells is transforming (Figures 2f and g), and that this transformation is inhibited by either pharmacological JAK inhibition or short hairpin RNA-mediated knockdown of CRLF2 expression 61,73,74 (Figure 2h). Similarly, studies using primary murine hematopoietic progenitors have shown that enforced expression of CRLF2 alone promotes lymphoid expansion, but this is insufficient to result in the development of leukemia 71 (and unpublished data).…”

“…61,71,73,74 Over half of CRLF2-rearranged cases harbor activating JAK1 or JAK2 mutations, and conversely, nearly all JAK-mutated cases have CRLF2 rearrangements, suggesting that these lesions together contribute to leukemogenesis. Importantly, in non-DS-ALL, CRLF2 alteration and JAK mutations are associated with the presence of IKZF1 alterations, and several studies have observed strong associations between CRLF2/JAK alterations and very poor outcome, 70,77 suggesting that JAK inhibition may be a useful therapeutic approach in these highrisk cases that at present frequently fail maximal therapy.…”

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

“…Previous studies by our group and others revealed differences between the genetics of DS-ALLs and of sporadic ALLs (3)(4)(5)(6). The typical cytogenetic subgroups, ETV6-RUNX1 and hyperdiploid ALLs, are less common in DS-ALLs.…”