CDKN2 Gene Deletion As Poor Prognosis Predictor Involving in the Progression of Adult B-Lineage Acute Lymphoblastic Leukemia Patients

Background: Genes CDKN2A (MTS1) and CDKN2B (MTS2), which encode for p16INK4a/p14ARF and p15INK4b respectively from the 9p21.3 locus, are thought to be an important growth suppressor gene. INK4a/ARF regulates p53 tumor suppressor function by interacting with MDM2. P15/INK4b works as a CDK inhibitor, which inhibits phosphorylation of Rb by inactivating cyclin/ CDK-4/6 complexes and thereby controls cell-cycle G1 progression. Deletion of CDKN2A/B was well known in many hematologic malignancies, but only few report investigated this deletion effect on clinical prognosis.

Methods: This study performed analysis of the CDKN2 deletion in 215 adult B-ALL patients, and relation with cytogenetic prognostic factors (BCR/ABL; E2A/PBXl; TEL/AML1; MLL rearrangement; MYC, IGH translocation).

Results: The prevalence of CDKN2 deletions in all study population was 28.4%. There is no difference between patients with CDKN2 deletion and wild-type patients in sex, age, white blood cells(WBC) count, BM blast percentage,extra infiltration and induction complete remission(CR) rate. Analysis at relapse patients revealed increased rate of CDKN2 loss (44.6%) compared with the rate in all patients (28.4%) (p=0.006). Deletions of CDKN2 were significantly associated with poor outcomes including decreased overall survival (OS) (p<0.001), lower disease free-survival (DFS) (p<0.001), and increased cumulative incidence of relapse (p=0.002); Also, CDKN2 deletions were strongly associated with IGH translocation (p=0.021); and had an adverse effect on patients who with BCR-ABL fusion gene or MLL rearranged. Among of patients with the CDKN2 deletions , the subgroup of received Allo-HSCT treatment had a better OS and DFS compared with the subgroup received chemotherapy only (OS: p<0.000; DFS: p<0.000).

Conclusion: Patients with CDKN2 gene deletion were benefited from allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Deletion of CDKN2 gene was commonly observed through leukemia progression and was a possible poor prognostic marker in long-term outcomes.