Prognostic implications of cyclins (D1, E, A), cyclin‐dependent kinases (CDK2, CDK4) and tumor‐suppressor genes (pRb, p16INK4A) in childhood acute lymphoblastic leukemia

Abstract

Immunohistochemistry was used to analyze samples of 40 newly diagnosed childhood acute lymphoblastic leukemias (ALL) for their expression of cyclins (D1, E, A), cyclindependent kinases (cdk2, cdk4) and tumor-suppressor genes (pRb, p16 INK4A ), in order to discover whether or not the expression of these various proteins may be of prognostic relevance for the survival of children with ALL. Patients with ALL who were strongly positive for cyclin D1 had a lower probability of remaining in first continuous remission than ALL patients who were negative or weakly positive for this trait. There was also a significant correlation between expression of cyclin D1 and frequency of recurrence. For cyclin E and cyclin A, in contrast, there was no difference in the duration of relapse-free-intervals or the frequency of recurrence in patients. Children with cdk4-positive ALL had a lower probability of remaining in first continuous remission than children with cdk4-negative ALL. No prognostic relevance was found for cdk2. Patients with ALL who expressed pRb had a higher probability and patients who expressed p16 a lower probability of remaining in first continuous remission, but the results were not statistically significant. This investigation demonstrated that cyclin D1 and cdk4 were the most important prognostic factors for children with ALL, and that the combination of them showed the strongest prognostic relevance.

Activation of Wnt/β‐catenin pathway mediates growth and survival in B‐cell progenitor acute lymphoblastic leukaemia

“…Many of the known Wnt targets are proto‐oncogenes, such as CCND1 , MYC , BIRC5 and ID2 (He et al , 1998; Tetsu & McCormick, 1999; Rockman et al , 2001; Zhang et al , 2001), and have been identified in colon cancer cells, but to date there are only a limited number of studies that have examined target gene expression in lymphoid cells (Staal et al , 2004; Nygren et al , 2007). Surprisingly, we did not detect regulation of the commonly regulated targets including CCND1 or BIRC5 , and it is possible that these genes are already deregulated in the ALL cells tested (Volm et al , 1997; Mori et al , 2002). However, it is also possible that these genes may not be the strong direct targets of Wnt signalling that has been assumed.…”

Relationship of p15 and p16 gene alterations to elevated dihydrofolate reductase in childhood acute lymphoblastic leukaemia

“…However, our findings that changes in DHFR were not entirely reflective of p15 levels in an in vitro expression model, and that no relationship was apparent between p15/p16 gene status and DHFR levels for approximately 50% of our BP‐ALLs, argue that other factors must come into play in regulating this critical enzyme target. Indeed, changes in the levels (or activities) of any of a number cell cycle regulatory proteins [including cyclin D1 (Hochhauser et al , 1996), CDKs (Schulze et al , 1994; Volm et al , 1997), Rb (Li et al , 1995; Sauerbrey et al , 1996), E2F transactivators (Lukas et al , 1996), p53 (Yeargin et al , 1993) and MDM‐2 (Bueso‐Ramos et al , 1993)] could potentially exert profound effects on DHFR catalytic activity and MTX sensitivity and, similarly, obviate the inhibitory effects of p15 and/or p16 on downstream pathways. Of particular interest is p14 ARF , also encoded by the p16 gene locus, which directly affects the p53 pathway by stabilizing p53 and MDM2 (Stott et al , 1998; Taniguchi et al , 1999).…”

Alteration of cell-cycle regulation in epithelial ovarian cancer

“…CDK4 overexpression is inversely correlated with p16 (17) and positively correlated with cyclin D1 (38) . The prognostic significance of CDK4 expression in ovarian cancer has not been elucidated, although it is an important prognostic factor in acute lymphocytic leukemia and esophageal squamous cell carcinoma (43,44) .…”