Acute lymphoblastic leukemia (ALL) is the most common malignancy in children (prevalence of approximately 1:1500). Children with Down syndrome have a 10- to 20-fold increased risk of developing acute leukemia. B-Cell dependent BCR-ABL1-like ALL, also known as Philadelphia chromosome (Ph)-like ALL, is a high-risk subset with a gene expression profile which shares significant overlap with that of Ph-positive (Ph+) ALL, but lacking the BCR-ABL1 fusion. In 2017, the WHO recognized BCR-ABL1-like ALL as a new entity.
Chromosomal rearrangements resulting in the overexpression of cytokine receptor like factor 2 (CRLF2) can be found in up to 50% of BCR-ABL1-like ALL cases. The CRLF2 gene is located in the pseudoautosomal region 1 (PAR1) of the X and the Y chromosome. Three genetic key mechanisms regarding CRLF2 and ALL are known. Firstly, the CRLF2 gene is placed under the control of the IGH enhancer. Translocations of the type t(X;14) or t(Y;14) are the genetic basis for this aberration. Secondly, fusion of CRLF2 to CSF2RA, a further PAR1 gene, has been described. Thirdly, cryptic interstitial deletions juxtaposing the initial non-coding exon of the purinergic receptor P2Y8 (P2RY8) and CRLF2 have been shown. The resulting P2RY8-CRLF2 fusion under the control of the P2RY8 promoter is strongly transcribed in lymphoid cells. CRLF2 rearrangements result in increased protein levels, which initiate significantly enhanced JAK/STAT signaling, whereby disproportionate JAK and subsequent STAT5 activation induces strongly enhanced B-cell activation and proliferation.
XL CRLF2 BA detects chromosomal aberrations resulting from CRLF2 gene rearrangements (deletions and translocations).
XL P2RY8 del (D-5150-100-OG) can be used as an additional tool in order to detect the presence of the P2RY8-CRLF2 fusion gene.
Clinical Applications
- Acute Lymphoblastic Leukemia (ALL)