We demonstrated the association of IKZF1 polymorphism rs4132601 T/G with increased risk of ALL among Tunisian pediatric cohort, with altered phenotypic changes among ALL patients.
Common CNAs involved CDKN2A/2B (30.3%), IKZF1 (27.3%), PAX5 (9.1%), RB1 (9.1%), BTG1 (6.7%), and ETV6 (6.7%), which regulate cell cycle, B lymphopoiesis, or act as tumor suppressors in ALL.
In this issue of Cancer Cell, Churchman et al. add to the list of leukemia predisposition genes with the identification and characterization of germline IKZF1 variants in childhood ALL.
The multiplex ligation-dependent probe amplification (MLPA) method was used to detect the copy number alterations (CNAs) of IKAROS family zinc finger 1 (<i>IKZF1</i>), paired box 5 (<i>PAX5</i>), ETS variant 6 (<i>ETV6</i>), RB transcriptional corepressor 1 (<i>RB1</i>), BTG anti-proliferation factor 1 (<i>BTG1</i>), early B-cell factor 1 (<i>EBF1</i>), cyclin dependent kinase inhibitor 2A/2B (<i>CDKN2A/2B</i>) and cytokine receptor like factor 2 (<i>CRLF2</i>) genes in 87 adults with acute lymphoblastic leukemia (ALL) in China.
Our results demonstrate that the IKAROS promotes PHF2 expression, and suggest that PHF2 <sup>low</sup> expression works with the IKAROS gene deletion to drive oncogenesis of ALL.
These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL.
Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial.
The present study examines the incidence of IKZF1, CDKN2A/B, PAX5, EBF1, ETV6, BTG1, RB1, JAK2, and Xp22.33 gene deletions/duplications associated with pediatric ALL in Iran and investigates the possible effect of these mutations on drug resistance.
Recent experimental mouse modeling of B-progenitor ALL has shown that IKZF1 alterations have multiple effects, including arresting differentiation, skewing lineage of leukemia from myeloid to lymphoid, and, in Ph+ leukemia, conferring resistance to tyrosine kinase inhibitor (TKI) therapy without abrogating ABL1 inhibition.
The IKZF1 SNPs, rs10235796 and rs6964969, and the CDKN2A SNP rs3731246 (previously unreported) could serve as risk markers for ALL susceptibility in Yemeni children.
CFZ showed significantly higher activity than BTZ in the majority of ALL cell lines except for the P-glycoprotein-positive t(17;19) ALL cell lines, and IKZF1 deletion was also associated with a favorable response to CFZ treatment.
Philadelphia chromosome-like ALL is essentially heterogeneous; however, deletion mutations in the IKZF1 gene encoding the transcription factor IKAROS underlie many cases as a key factor inducing aggressive phenotypes and poor treatment responses.
Previous studies have shown evidence for association between risk of ALL and variation within IKZF1, ARID5B, CEBPE, CDKN2A, GATA3, and BM1-PIP4K2A genes.
Recent genome-wide association studies (GWAS) focusing on pediatric acute lymphoblastic leukemia (ALL), the most common malignancy in children younger than 15 years old, have found evidence that single-nucleotide polymorphisms (SNPs) in IKZF1 (7p12.2), ARID5B (10q21.2), CDKN2A (9p21.3), and CEBPE (14q11.2) are strongly associated to the risk of developing pediatric ALL.
The current case-control study evaluated variants in ARID5B (rs7089424, rs10821936), IKZF1 (rs4132601) and CEBPE (rs2239633) genes, which appear most significantly associated with risk of developing childhood B-lineage ALL.
In the present study, we aimed to inspect the impact of IKZF1 gene polymorphisms and childhood ALL in a sample of Iranian population who live in south east of Iran.
Our data also suggest that high CRLF2 expression works with the IKZF1 deletion to drive oncogenesis of ALL and has significance in an integrated prognostic model for adult high-risk ALL.
These SNPs are located at CDKN2A (rs3731217) and IKZF1 (rs4132601), genes frequently lost in ALL, and at CEBPE (rs2239633), ARID5B (rs7089424), PIP4K2A (rs10764338), and GATA3 (rs3824662), genes located on chromosomes gained in high-hyperdiploid ALL.