The presence of homozygous deletion of p16/INK4A, p14/ARF, p15/INK4B, and heterozygous deletion of WT1 locus remained stable in the leukemia throughout phenotypic switch, revealing that this AML can be genetically associated to T-ALL.
Consistently, these leukaemias show lower frequencies of prototypical T-ALL lesions such as CDKN2A/B deletions and activating mutations in NOTCH1 and show a higher prevalence of mutations typically associated with the pathogenesis of acute myeloid leukaemias (AMLs).
Retention of Arf had relatively modest activity in suppressing the formation of T-ALLs arising from bone marrow-derived ICN1+ progenitors in which the locus is epigenetically silenced, and all resulting Arf (+/+) tumors failed to express the p19(Arf) protein.
A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups.
T-cell acute lymphoblastic leukemia cells designed to conditionally express p16(INK4A) arrest in the G(0)/G(1) phase of the cell cycle and show increased sensitivity to glucocorticoid- and tumor necrosis factor receptor superfamily 6-induced apoptosis.
Inactivation of the CDKN2 genes that encode the p16(INK4A) and p14(ARF) proteins occurs in the majority of human T-cell acute lymphoblastic leukemias (T-ALLs).
Cloning and sequencing of the p16gamma cDNA revealed that p16gamma was identical to p16(INK4A), except that it contained an in-frame insertion of 197 bp between exons 2 and 3. p16gamma expression was detected in the majority of p16(INK4A)-expressing primary T-ALL and B-ALL patient samples and other p16(INK4A)-expressing tumor samples, but was only barely detectable in some normal mononuclear cells and other non-tumor samples.
Here we describe the identification of another ABL1 fusion, EML1-ABL1, in a T-ALL patient with a cryptic t(9;14)(q34;q32) associated with deletion of CDKN2A (p16) and expression of TLX1 (HOX11).
The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression and deletion of CDKN2A, consistent with a multistep pathogenesis of T-ALL.
To investigate possible consequences of this genetic alteration for tumor development, we conditionally expressed p16(INK4A) in the T-cell acute lymphoblastic leukemia line CCRF-CEM, which carries a homozygous deletion of this gene.
We show here that overexpression of p18(INK4c) does not block cell cycle progression in a T-cell acute lymphocytic leukemia cell line (CEM) sensitive to p16(INK4a)-mediated G(1) arrest.
The homozygously deleted p16T-ALL patients (n = 34) treated with the modern multiagent chemotherapy schemes of the Dutch Childhood Leukaemia Study Group ALL-VII/-VIII or Co-operative ALL-92/-97 protocols have a significantly lower 5-year disease-free survival (DFS) than germ-line p16T-ALL (n = 25) (65.1 +/- 9.1% vs. 95.5 +/- 4.4%, Plog rank = 0.021).
Detection of methylthioadenosine phosphorylase (MTAP) and p16 gene deletion in T cell acute lymphoblastic leukemia by real-time quantitative PCR assay.
We reported previously that in T-cell acute lymphoblastic leukemia (T-ALL), p16 and p15 were frequently (approximately 70%) inactivated at the DNA level by deletion, mutation, or hypermethylation.
Transduction of p16INK4a-negative T-ALL lines with retrovirus encoding p16INK4a significantly inhibited their in vitro proliferation by inducing G1-arrest.
We therefore analyzed the clinical and biological implications of this feature by studying p16ink4a expression in 58 cases of childhood ALL. mRNA and protein were significantly correlated and both appeared more highly expressed in B than in T lineage ALLs: 13 out of the 15 T cell ALLs did not show any p16ink4a expression.
Disruption of the multiple tumor suppressor gene MTS1/p16(INK4a)/CDKN2 by illegitimate V(D)J recombinase activity in T-cell acute lymphoblastic leukemias.