Highlights
CRLF2
overexpression associates with
IKZF1
deletions that lead to a dominant-negative effect and with
IKZF1
plus.
Paediatric patients with a high load expression of IK4 isoform presented higher
CRLF2
transcript levels.
CRLF2
overexpression and
IKZF1
deletions conferred poorer prognosis both to paediatric patients treated with RELLA05 protocol as well as to adult patients.
This narrative review describes implementation, current status and perspectives of a pharmacogenomic (PGx) program at the Brazilian National Cancer Institute (INCA), targeting the cancer chemotherapeutic drugs – fluoropyrimidines, irinotecan and thiopurines. This initiative, designed as a research project, was supported by a grant from the Brazilian Ministry of Health. A dedicated task force developed standard operational procedures from recruitment of patients to creating PGx reports with dosing recommendations, which were successfully applied to test 100 gastrointestinal cancer INCA outpatients and 162 acute lymphoblastic leukemia pediatric patients from INCA and seven other hospitals. The program has been subsequently expanded to include gastrointestinal cancer patients from three additional cancer treatment centers. We anticipate implementation of routine pre-emptive PGx testing at INCA but acknowledge challenges associated with this transition, such as continuous financing support, availability of trained personnel, adoption of the PGx-informed prescription by the clinical staff and, ultimately, evidence of cost–effectiveness.
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.
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