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CRLF2 overexpression defines an immature‐like subgroup which is rescued through restoration of the PRC2 function in T‐cell precursor acute lymphoblastic leukemia

CRLF2 overexpression has been described as a biomarker of poor prognosis in T‐cell acute lymphoblastic leukemia (T‐ALL). In the present study, we aimed to unravel the genomic profile underlying CRLF2 overexpression (CRLF2‐high) by analyzing RNA‐seq, WES, and SNP‐array data from 264 T‐ALL patients and five cell lines deposited on the TARGET initiative, Cancer Cell Line Encyclopedia and Gene Expression Omnibus. These data allowed us to delineate the genomic landscape of CRLF2‐high in T‐ALL, which was associated with PTEN, JAK3, PHF6, EZH2, and RUNX1 mutations. We also observed an enrichment of CRLF2‐high in early T‐precursor (ETP)‐ALL (23.08% vs. 4.02%, P = 7.579e−06) and a very similar gene upregulation profile between these two entities. The inhibition of BET (iBET) proteins is a strategy previously demonstrated to reverse the gene upregulation pattern of ETP cells through restoration of polycomb repressive complex 2 (PRC2) activity. While CRLF2 expression was rescued by using this strategy in LOUCY (untreated vs. iBET P = 0.0095, DMSO vs. iBET P = 0.0286), a classical ETP‐ALL cell line, PRC2 loss was not sufficient to promote CRLF2 upregulation in JURKAT, a more mature T‐ALL cell line. Considering the role of IKZF1 in CRLF2 regulation and in recruitment of PCR2, we evaluated IKZF1 status according to CRLF2‐expression subgroups. We identified that IKZF1 transcripts with intron retention were upregulated in the CRLF2‐high subgroup. Here, we delineated the gene expression profile of CRLF2‐high T‐ALL samples and unraveled the crucial role of PRC2 in CRLF2 regulation in ETP‐ALL.