At the 9p arm is located the p16 (MTS1) TSG and probably others with an effect on various human tumours such as acute lymphoblastic leukaemia, bladder cancer, gliomas, malignant mesotheliomas, melanomas and non-small cell lung carcinomas.
Since most hematological malignancies-except ALL-are infrequently associated with p16INK4A and retinoblastoma (Rb) gene alteration it seems worthwhile to explore cdk4 and cdk6 expression to determine whether or not the disruption of the p16INK4A/Rb/cdk4/cdk6 regulatory loop might play a role in their pathogenesis.
Homozygous deletions of p16 exons were found in 5 of 10 (50%) patients with CML in lymphoid BC and in 5 (26%) ALL patients, but in only 1 (2%) case with AML.
We analyzed p16INK4A and p15INK4B genes in 178 cases of primary leukemias including 81 cases of chronic lymphocytic leukemia (CLL), seven of hairy cell leukemia (HCL), seven of chronic myelogenous leukemia (CML), 43 of acute myelogenous leukemia (AML), 27 of acute lymphoblastic leukemia (ALL), and 13 of myelodysplastic syndrome (MDS) by Southern blot analyses.
Single stranded conformation polymorphism analysis of exons 1 and 2 of the p16 gene was performed in 88 cases of ALL, including the 63 patients analyzed by Southern blot.
In the cell lines, the homozygous deletion of the CDK4I gene was detected in a variety of cell lineages, whereas all 4 cases showing the homozygous deletion were confined to ALL.
Homozygous MTS2 deletions were observed in 16 of 24 T-ALL cases and in 1 of 31 B-lineage ALLs (P < .001), all of them displaying homozygous MTS1 deletions.
We observed a higher frequency of MTS1 deletions in ALL than in NHL (P < 0.001) and in T-cell neoplasms compared to B-cell neoplasms (67% v 6%; P = 0.001).
We conclude that hemizygous or homozygous deletions of the CDKN2 gene occur at high frequency in T-ALL and at low frequency in B-lineage ALL, supporting the role of this gene as a tumour suppressor, especially in T-ALL.
In order to determine whether these genes are more widely involved in haematological malignancies, we have investigated a total of 84 samples that did not have homozygous p16 or p15 deletions from patients with acute lymphoid leukaemia (n=13), acute myeloid leukaemia (n=24) and chronic myeloid leukaemia in blast crisis (n=43) as well as four haemopoietic cell lines. p15 and p16 exon 1 and exon 2 were amplified by polymerase chain reaction (PCR), analysed by single-stranded conformation polymorphism (SSCP) and subsequently by sequencing.
To address this issue, we determined whether the CDKN2 gene deletions found in acute lymphoblastic leukemia (ALL) cell lines are also detected in the primary leukemia samples.
The high incidence of p16(INK4A) gene deletions in pediatric T cell lineage ALL suggests that this genetic alteration could represent an early and key event in the development of such a malignancy but it should not have any prognostic value.
In particular, we will discuss these aspects in the light of the role of p16INK4 gene inactivation in the development of human acute lymphoblastic leukemias.
Six of 12 cell lines, including acute lymphoblastic leukemia (ALL) lines of T-cell (three of four), of precursor-B cell (two of four) and of mixed phenotype (one of four), showed homozygous deletion of the p16 gene using PCR and Southern blotting.
Homozygous deletions of p16/MTS1 and p15/MTS2 genes are frequent in t(1;19)-negative but not in t(1;19)-positive B precursor acute lymphoblastic leukemia in childhood.
These data show the coexistence of multiple genetic defects in childhood B-lineage ALL Cell lines with t(12;21) will facilitate the study of TEL-AML1 and AML1-TEL fusion proteins as well as TEL and CDKN2 gene inactivation in leukemia transformation and progression.
In ALL an association of homozygous deletions of p16ink4a and p15ink4b, and T-lineage, 9p abnormalities, and prognostic factors was found in some but not all reports.
To determine if p19 genetic alterations play a role in hematopoietic malignancies, we examined DNA from 45 childhood newly diagnosed acute lymphocytic leukemias (ALLs), 30 acute myeloblastic leukemias (AMLs), 10 chronic myelocytic leukemias (CMLs), 45 adult T cell leukemias (ATLs), 70 non-Hodgkin's lymphomas (NHLs), and 20 multiple myelomas (MM) as well as 14 ALL, 20 AML, two ATL, and five lymphoma cell lines.