Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Abnormalities of the p16INK4a gene in childhood B-precursor acute lymphoblastic leukemia without nonrandom translocations: analysis of seven matched pairs of primary leukemia and corresponding cell line

Leukemia volume 15, pages 1136–1139 (2001)Cite this article

Progression of the cell cycle in eukaryotic cells is strictly and skillfully regulated by the sequential formation, activation, and subsequent inactivation of a series of cyclin and cyclin-dependent kinase (CDK) complexes. The activation of CDK4 and CDK6 by cyclin D elicits phosphorylation of retinoblastoma protein (pRB), which results in release of several pRB-associated transcription factors required for G1 to S phase progression. Among a family of proteins that bind and inhibit CDKs, p16INK4a specifically blocks the activity of CDK4 and CDK6 ultimately resulting in inhibition of cell division. The p16 gene located on chromosomal region 9p21 appears to be inactivated in a wide variety of tumors, and mice carrying a targeted deletion of p16 demonstrate development of spontaneous tumors at a high rate, suggesting that p16 could be a tumor suppressor. The human p16 gene locus encodes a second protein p14ARF via transcription of an alternative first exon and common exon 2 in different reading frame. This protein does not directly bind and inhibit CDKs but appears to enhance the functional activity of wild-type p53. Because mice with disrupted p19ARF (the mouse homologue of p14ARF) but intact p16 expression have a susceptibility to cancer, p14ARF is considered as another tumor suppressor. Among mechanisms that inactivate p16 in tumor cells, homozygous deletion may predominantly contribute to tumorigenesis or disease progression, because this inactivates both p16 and p14ARF that act upstream of pathways involving pRB and p53, respectively. However, there are some controversies regarding the significance of the p16 gene deletion, because the frequencies appear to be much lower in primary tumors than in cell lines. In acute lymphoblastic leukemia (ALL), the reported percentages of homozygous deletion in patients’ samples and cell lines are 14–29% and 70%, respectively.1,2,3 There could be two possible explanations for these discrepancies. One is that homozygous deletion of p16 is specifically associated with the biological nature of high grade malignancy, which leads not only to the high rate of relapse and the disease progression in vivo but also to the cell line establishment in vitro. The other is that this genomic loss occurs during the process of cell culture for the cell line establishment, and therefore this transformation in vitro should be called an artifact. To address this, Kees et al4 examined the p16 gene status in 12 matched pairs of primary leukemia sample and corresponding cell line, and found that the status was identical in each pair, indicating that loss of the p16 gene is not an artifact. In their study, two of four pairs from B-precursor ALL had intact p16 alleles and the other two pairs had homozygous deletion. However, no additional studies on the p16 gene status using pairs of primary leukemia sample and corresponding cell line have been performed. To address the biological and clinical significance of p16 abnormalities in childhood B-precursor ALL without nonrandom translocations, we investigated the p16 gene status in seven matched pairs of primary leukemia and corresponding cell line.

Seven pairs of primary sample and cell line from childhood B-precursor ALL without nonrandom translocations such as 9;22, 11q23-related, and 1;19 translocations were available and used in this study. The patients, all females aged 6 to 13 years (median 10) with peripheral white blood cells ranging from 3.4 to 191.8 × 109/l (median 69.8), were diagnosed to have B-precursor ALL (CD10+, CD19+, CD13−, HLA-DR+, sIg−) and received chemotherapy according to the protocol by Tokyo Children's Cancer Study Group. Patient 4 has maintained first complete remission for 89 months, but the other six patients relapsed at 3–18 months (median 7) and died at 7–25 months (median 12) from the onset. Four cell lines (KOPN-39, -61, -71, -75) were derived from bone marrow (BM) samples at initial diagnosis of patients 1–4, while another three cell lines (KOPN-40, -47, -70) were derived from BM samples at first relapse of patients 5–7. Results of cytogenetic analysis on patient samples at onset and established cell lines were summarized in Table 1. Although karyotypic abnormalities that clearly affect the 9p21 region were not revealed in five patient samples examined, they were detected in five of seven cell lines. BM cells from patients 4 and 5 were reported to have normal karyotype, but corresponding cell lines showed karyotypic abnormalities that affect 9p21.

Table 1 Analysis of karyotype and the p16 gene in primary cells and established cell lines
Full size table

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Quesnel B, Preudhomme C, Philippe N, Vanrumbeke M, Dervite I, Lai JL, Bauters F, Wattel E, Fenaux P . p16 gene homozygous deletions in acute lymphoblastic leukemia Blood 1995 85: 657–663

    CAS  PubMed  Google Scholar 

  2. Ogawa S, Hangaishi A, Miyawaki S, Hirosawa S, Miura Y, Takeyama K, Kamada N, Ohtake S, Uike N, Shimazaki C, Toyama K, Hirano M, Mizoguchi H, Kobayashi Y, Furusawa S, Saito M, Emi N, Yazaki Y, Ueda R, Hirai H . Loss of the cyclin-dependent kinase 4-inhibitor (p16; MTS1) gene is frequent and highly specific to lymphoid tumors in primary human hematopoietic malignancies Blood 1995 86: 1548–1556

    CAS  PubMed  Google Scholar 

  3. Siebert R, Willers CP, Schramm A, Fossa A, Gana Dresen IM, Uppenkamp M, Nowrousian MR, Seeber S, Opalka B . Homozygous loss of the MTS1/p16 and MTS2/p15 genes in lymphoma and lymphoblastic leukemia cell lines Br J Haematol 1995 91: 350–354

    Article  CAS  Google Scholar 

  4. Kees UR, Ranford PR, Hatzis M . Deletions of the p16 gene in pediatric leukemia and corresponding cell lines Oncogene 1996 12: 2235–2239

    CAS  PubMed  Google Scholar 

  5. Maloney KW, McGavran L, Odom LF, Hunger SP . Acquisition of p16INK4A and p15INK4B gene abnormalities between initial diagnosis and relapse in children with acute lymphoblastic leukemia Blood 1999 93: 2380–2385

    CAS  PubMed  Google Scholar 

  6. Nakamura M, Sugita K, Inukai T, Goi K, Iijima K, Tezuka T, Kojika S, Shiraishi K, Miyamato N, Karakida N, Kagami K, O-Koyama T, Mori T, Nakazawa S . p16/MTS1/INK4A gene is frequently inactivated by hypermethylation in childhood acute lymphoblastic leukemia with 11q23 translocation Leukemia 1999 13: 884–890

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Yamanashi, Medical University, Yamanashi, Japan

    M Nakamura, K Sugita, T Inukai, K Goi, N Miyamoto, K Kagami, M Saito & S Nakazawa

  2. Department of Pediatrics, Saitama, Shakaihoken Hospital, Saitama, Japan

    T Okazaki-Koyama & T Mori

Authors
  1. M Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Sugita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Inukai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Goi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Kagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Okazaki-Koyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Nakazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakamura, M., Sugita, K., Inukai, T. et al. Abnormalities of the p16INK4a gene in childhood B-precursor acute lymphoblastic leukemia without nonrandom translocations: analysis of seven matched pairs of primary leukemia and corresponding cell line. Leukemia 15, 1136–1139 (2001). https://doi.org/10.1038/sj.leu.2402160

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402160

Search

Advanced search

Quick links