The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives initiation, clonal expansion and metastasis. In this process, alterations in genes encoding proteins that govern processes such as cell proliferation, differentiation, and growth provide us with some of the clearest mechanistic insights into how and why cancer arises. In such a scenario, deletions in the 9p21.3 cluster involving CDKN2A/ARF/CDKN2B genes arise as one of the oncogenic hallmarks of ALL. Deletions in this region are the most frequent structural alteration in T-cell acute lymphoblastic leukemia (T-ALL) and account for roughly 30% of copy number alterations found in B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). Here, we review the literature concerning the involvement of the CDKN2A/B genes as a prognosis marker of good or bad response in the two ALL subtypes (BCP-ALL and T-ALL). We compare frequencies observed in studies performed on several ALL cohorts (adult and child), which mainly consider genetic data produced by genomic techniques. We also summarize what we have learned from mouse models designed to evaluate the functional involvement of the gene cluster in ALL development and in relapse/resistance to treatment. Finally, we examine the range of possibilities for targeting the abnormal function of the protein-coding genes of this cluster and their potential to act as anti-leukemic agents in patients.

Prognostic heterogeneity of adult B‐cell precursor acute lymphoblastic leukaemia patients with t(1;19)(q23;p13)/TCF3‐PBX1 treated with measurable residual disease‐oriented protocols

“…Unfortunately, detailed genomic data are not available, although the ACA could indicate the presence of recurrent abnormalities with potential poor outcome (i.e. MYB , CDKN2A/B and RB1 ) 13,14 . Besides MRD, genetic differences at the molecular level might contribute, at least in part, to the different outcomes observed among patients with TCF3‐PBX1 .…”

B‐cell acute lymphoblastic leukaemia: recent discoveries in molecular pathology, their prognostic significance, and a review of the current classification

“…CDKN2A/B deletions are more frequently found in association with BCR‐ABL1 + and BCR‐ABL1 ‐like ALL. CDKN2A/B losses are associated with an inferior outcome in adults, but do not appear to affect the outcome in paediatric ALL 93 .…”

“…These may be homozygous or heterozygous deletions, commonly involve both CDKN2A and CDKN2B , as well as PAX5 deletions given their co‐location on chromosome 9p. Promoter methylation alterations are also described, though they are less common than gene deletions 25,93 . CDKN2A/B deletions are more frequently found in association with BCR‐ABL1 + and BCR‐ABL1 ‐like ALL.…”

“…Promoter methylation alterations are also described, though they are less common than gene deletions. 25,93 CDKN2A/B deletions are more frequently found in association with BCR-ABL1 + and BCR-ABL1-like ALL. CDKN2A/B losses are associated with an inferior outcome in adults, but do not appear to affect the outcome in paediatric ALL 93 .…”

Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children

“…The prevalence of these alterations ranges from 0 to 40% in the pediatric population. Very few studies have analyzed the effect of methylation status in the CDKN2A/B promoters, most of which have not shown a significant effect on BCP-ALL progression [ 267 ].…”