Absence of Mutations in the CDKN2 Binding Site of CDK4 in Childhood Acute Lymphoblastic Leukemia

Einsiedel, Hagen Graf; Taube, Tillmann; Beyermann, Birgit; Dragon, Serge; Möricke, Anja; Kebelmann-betzig, Christian; Köchling, Joachim; Henze, Günter; Seeger, K.

doi:10.3109/10428190109057941

Cited by 3 publications

(3 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the causal role of these alterations in tumor development is difficult to assess [25]. Present study revealed that there was no germline mutation in codon 24 and 22 of CDK4 and these results support the findings of previous studies [20,26,27]. The potentially dominant Arg24Cys mutation of CDK4 was not detected in Indian patients with squamous cell carcinoma of head and neck [8].…”

Section: Discussionsupporting

confidence: 88%

Novel germline CDK4 mutations in patients with head and neck cancer

Sabir

Baig

Mahjabeen

et al. 2012

Hered Cancer Clin Pract

View full text Add to dashboard Cite

BackgroundCyclin-dependent kinase 4 (CDK4) together with its regulatory subunit cyclin D1, governs cell cycle progression through G1 phase. Cyclin-dependent kinase inhibitors, including p16INK4A in turn regulate CDK4. In particular, deregulation of the p16/CDK4/cyclin D1 complex has been established in a variety of human tumors including gliomas, sarcomas, melanoma, breast and colorectal cancer. However, changes in CDK4 have rarely been observed.MethodIn this study we used a combination of PCR-SSCP and direct sequencing for mutational screening of CDK4. DNA was isolated from peripheral blood leukocyte of patients with squamous cell carcinoma of head and neck, for screening germline mutations in coding regions of CDK4.ResultsVariations observed in exon 2 and 5 were three missense mutations, g5051G > C (Ser52Thr), g5095G > C (Glu67Gln), g5906C > A, g5907C > G (Pro194Ser) and novel frame shift mutations g7321_23delTGA, g7121_7122insG, g7143delG in exon 7 and 3′UTR respectively.ConclusionIn conclusion, two novel mutations were found in N terminal domain which indicates that CDK4 mutation may play a major role in the development and progression of squamous cell carcinoma of head and neck.

show abstract

Section: Discussionsupporting

confidence: 88%

Novel germline CDK4 mutations in patients with head and neck cancer

Sabir

Baig

Mahjabeen

et al. 2012

Hered Cancer Clin Pract

View full text Add to dashboard Cite

show abstract

“…S1). Ptpn11 and Cdk4 mutations have been shown previously to activate RAS signaling and cell cycle regulation, respectively, in human AML ( 11 , 20 ). Single-mutant cases were observed for several genes (fig.…”

Section: Resultsmentioning

confidence: 93%

“…Single-mutant cases were observed for several genes (fig. S1 and table S1), including for instance in Hras and Braf, that have also previously been reported to be mutated in AML (6,10,11,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Last, to determine whether the C883T/R295C was dependent on the transplantation setting, we interrogated 10 separate iMLL-ENL AML samples derived from an alternative, non-transplantation-based model system (32).…”

Section: Imll-enl Amls Associate With a Highly Recurrent Point Mutati...mentioning

confidence: 99%

A somatic mutation in moesin drives progression into acute myeloid leukemia

et al. 2022

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event. Upon clonal transformation, we identified and extensively verified a recurrent codon-changing mutation (Arg 295 Cys) in the ERM protein moesin that markedly accelerated leukemogenesis. Human cancer-associated moesin mutations at the conserved arginine-295 residue similarly enhanced MLL-ENL–driven leukemogenesis. Mechanistically, the mutation interrupted the stability of moesin and conferred a neomorphic activity to the protein, which converged on enhanced extracellular signal–regulated kinase activity. Thereby, our studies demonstrate a critical role of ERM proteins in AML, with implications also for human cancer.

show abstract

Absence of R24C Mutation of the CDK4 Gene in Leukemias and Solid Tumors

et al. 2003

View full text Add to dashboard Cite

A mutation of the p16(INK4a)-binding domain of the cyclin dependent kinase 4 (CDK4) gene, R24C, has been reported in some cases of melanoma. This mutation prevented binding of the CDK4 inhibitor p16(INK48) to CDK4. To determine the relevance of the mutation, we performed polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis in diverse types of human leukemias and solid tumors. No mobility shifts indicating sequence alterations were observed in 273 tumors and 49 cell lines from diverse kinds of tumors These results suggest that in contrast to melanoma, in many other types of human neoplasms the mutation of the CDK4 gene is very rare. To better understand these findings, we randomly mutagenized the CDK4 gene and used the yeast two-hybrid method to screen for CDK4 mutants that had lost the ability to bind to p16(INK4a). Sequence analysis and in vitro kinase assays showed that most of the mutations that disrupted interactions with p16(INK4) also knocked out the activity of CDK4. This result may explain the rareness of CDK4 mutations in human tumors.

show abstract

Absence of Mutations in the CDKN2 Binding Site of CDK4 in Childhood Acute Lymphoblastic Leukemia

Cited by 3 publications

References 22 publications

Novel germline CDK4 mutations in patients with head and neck cancer

Novel germline CDK4 mutations in patients with head and neck cancer

A somatic mutation in moesin drives progression into acute myeloid leukemia

Absence of R24C Mutation of the CDK4 Gene in Leukemias and Solid Tumors

Contact Info

Product

Resources

About