DOI: 10.1046/j.1365-2141.2001.02775.x. Relationship of p15 and p16 gene alterations to elevated dihydrofolate reductase in childhood acute lymphoblastic leukaemia

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

10.1046/j.1365-2141.2001.02775.x

Crossref journal-article

Wiley

British Journal of Haematology (311)

Abstract

The downstream effects of p15 and p16 gene deletions and loss of transcripts on dihydrofolate reductase (DHFR) were examined in 63 B‐precursor (BP) acute lymphoblastic leukaemia (ALL) samples. p15 and/or p16 gene deletions were seen in 6% and 8%, respectively, of BP‐ALL samples; however, losses of p15 and/or p16 transcripts were seen in 26 out of 63 (41%) samples. Loss of p15 transcripts (36·5%) exceeded that for p16 (17·5%). For the 26 BP‐ALLs that lacked p15 and/or p16 transcripts, only six (23%) exhibited low levels of DHFR by flow cytometry assay with Pt430, a fluorescent anti‐folate. Conversely, 18 out of 37 (49%) BP‐ALL samples with intact p15 and/or p16 genes and transcripts showed low levels of DHFR (P = 0·04). In p15‐ and p16‐null K562 cells transfected with a tetracycline‐inducible p15 cDNA construct, induction of p15 transcripts and protein was accompanied by decreased growth rates, decreased S‐phase fraction, decreased retinoblastoma protein phosphorylation, and markedly reduced levels of DHFR transcripts and protein. Collectively, our results suggest that losses of p15 and/or p16 gene expression result in elevated levels of DHFR in BP‐ALL in children. However, additional downstream factors undoubtedly also contribute to elevated levels of this enzyme target.

Bibliography

Shah, S. J., Taub, J. W., Witt, T. L., Pollock, B. H., Ding, B. C., Moore, D. S., Amylon, M., Pullen, J., Ravindranath, Y., & Matherly, L. H. (2001). Relationship of p15 and p16 gene alterations to elevated dihydrofolate reductase in childhood acute lymphoblastic leukaemia. British Journal of Haematology, 113(3), 746â756. Portico.

Authors 10

Sanjay J. Shah (first)
Jeffrey W. Taub (additional)
Teah L. Witt (additional)
Brad H. Pollock (additional)
Bee Ching Ding (additional)
Daniel S. Moore (additional)
Michael Amylon (additional)
Jeanette Pullen (additional)
Yaddanapudi Ravindranath (additional)
Larry H. Matherly (additional)

References 47 Referenced 5

{'key': 'e_1_2_6_2_1', 'first-page': '832', 'article-title': 'Frequent and selective methylation of p15 and deletion of both p15 and p16 in T‐cell acute lymphoblastic leukemia', 'volume': '57', 'author': 'Batova A.', 'year': '1997', 'journal-title': 'Cancer Research'} / Cancer Research / Frequent and selective methylation of p15 and deletion of both p15 and p16 in T‐cell acute lymphoblastic leukemia by Batova A. (1997)
10.1007/978-3-642-84895-7_23
10.1182/blood.V82.9.2617.2617
10.1083/jcb.59.3.766
10.1016/S0145-2126(97)00007-6
10.1038/sj.leu.2401043
10.1056/NEJM194806032382301
10.1016/S0021-9258(19)68121-4 / Journal of Biological Chemistry / Rapid formation of polyglutamyl derivatives of methotrexate and their association with dihydrofolate reductase as assessed by high pressure liquid chromatography in the Ehrlich ascites tumor cells by Fry D.W. (1982)
10.1182/blood.V86.2.677.bloodjournal862677
10.1016/0163-7258(85)90083-X
10.1056/NEJM199610033351408
10.1038/371257a0
{'key': 'e_1_2_6_14_1', 'first-page': '837', 'article-title': 'Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies', 'volume': '57', 'author': 'Herman J.G.', 'year': '1997', 'journal-title': 'Cancer Research'} / Cancer Research / Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies by Herman J.G. (1997)
10.1182/blood.V86.3.841.841
10.1093/jnci/88.18.1269
10.1126/science.8153634
10.1182/blood.V89.11.4161 / Blood / Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome by Kees U. (1997)
10.1182/blood.V90.11.4243
10.1200/JCO.1994.12.9.1939
10.1073/pnas.92.22.10436
10.1128/MCB.16.3.1047
10.1182/blood.V93.7.2380 / Blood / Acquisition of p16INK4A and p15INK4B gene abnormalities between initial diagnosis and relapse in children with acute lymphoblastic leukemia by Maloney K.W. (1999)
{'key': 'e_1_2_6_24_1', 'volume-title': 'Principles and Practice of Pediatric Oncology', 'author': 'Margolin J.F.', 'year': '1997'} / Principles and Practice of Pediatric Oncology by Margolin J.F. (1997)
10.3109/10428199609093433
{'key': 'e_1_2_6_26_1', 'first-page': '3420', 'article-title': 'Identification of a highly glycosylated methotrexate membrane carrier in K562 human erythroleukemia cells up‐regulated for tetrahydrofolate cofactor and methotrexate transport', 'volume': '51', 'author': 'Matherly L.H.', 'year': '1991', 'journal-title': 'Cancer Research'} / Cancer Research / Identification of a highly glycosylated methotrexate membrane carrier in K562 human erythroleukemia cells up‐regulated for tetrahydrofolate cofactor and methotrexate transport by Matherly L.H. (1991)
10.1182/blood.V85.2.500.500 / Blood / Elevated dihydrofolate reductase and impaired methotrexate transport as elements in methotrexate resistance in childhood acute lymphocytic leukemia by Matherly L.H. (1995)
10.1182/blood.V90.2.578
10.1182/blood.V85.9.2321.bloodjournal8592321 / Blood / Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute lymphoblastic leukaemia by Okuda T. (1995)
{'key': 'e_1_2_6_30_1', 'first-page': '1219', 'article-title': 'Universal inactivation of both p16 and p15 but not downstream components is an essential event in the pathogenesis of T‐cell acute lymphoblastic leukemia', 'volume': '6', 'author': 'Omura‐Minamisawa M.', 'year': '2000', 'journal-title': 'Clinical Cancer Research'} / Clinical Cancer Research / Universal inactivation of both p16 and p15 but not downstream components is an essential event in the pathogenesis of T‐cell acute lymphoblastic leukemia by Omura‐Minamisawa M. (2000)
10.1056/NEJM199808273390907
10.1016/S0021-9258(19)45359-3 / Journal of Biological Chemistry / A new fluorescent dihydrofolate reductase probe for studies of methotrexate resistance by Rosowsky A. (1982)
SAS Institute(1989)SAS/STAT User's Guide Version 6 4th edn Vol.2.SAS Institute Inc Cary NC.
10.1046/j.1365-2141.1996.d01-1753.x
{'key': 'e_1_2_6_35_1', 'first-page': '3475', 'article-title': 'Activation of the E2F transcription factor by cyclin D1 is blocked by p16INK4, the product of the putative tumor suppressor gene MTS1', 'volume': '9', 'author': 'Schulze A.', 'year': '1994', 'journal-title': 'Oncogene'} / Oncogene / Activation of the E2F transcription factor by cyclin D1 is blocked by p16INK4, the product of the putative tumor suppressor gene MTS1 by Schulze A. (1994)
10.1038/366704a0
10.1126/science.274.5293.1672
10.1200/JCO.1996.14.1.18
10.1093/emboj/17.17.5001
10.1006/bbrc.1997.6654
10.1182/blood.V86.2.755.bloodjournal862755 / Blood / Analysis of a family of cyclin‐dependent kinase inhibitors: p15/MTS2/INK4B,p16 /MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood by Takeuchi S. (1995)
10.1038/sj.leu.2401557
10.1002/(SICI)1097-0215(19971021)74:5<508::AID-IJC5>3.0.CO;2-7
10.1074/jbc.270.29.17468
10.1016/S0006-2952(96)00710-1
10.1016/S0006-2952(97)00639-4
10.1172/JCI116435
{'key': 'e_1_2_6_48_1', 'first-page': '2169', 'article-title': 'Reduced folate carrier gene expression in childhood acute lymphoblastic leukemia: relationship to immunophenotype and ploidy', 'volume': '4', 'author': 'Zhang L.', 'year': '1998', 'journal-title': 'Clinical Cancer Research'} / Clinical Cancer Research / Reduced folate carrier gene expression in childhood acute lymphoblastic leukemia: relationship to immunophenotype and ploidy by Zhang L. (1998)

Dates

Type	When
Created	22 years, 5 months ago (March 11, 2003, 1:34 a.m.)
Deposited	1 year, 11 months ago (Sept. 27, 2023, 11:13 a.m.)
Indexed	1 year, 10 months ago (Oct. 15, 2023, 7:50 p.m.)
Issued	24 years, 2 months ago (June 1, 2001)
Published	24 years, 2 months ago (June 1, 2001)
Published Online	23 years, 7 months ago (Jan. 12, 2002)
Published Print	24 years, 2 months ago (June 1, 2001)

Funders 0

None

BibTeX

@article{Shah_2001, title={Relationship of p15 and p16 gene alterations to elevated dihydrofolate reductase in childhood acute lymphoblastic leukaemia}, volume={113}, ISSN={1365-2141}, url={http://dx.doi.org/10.1046/j.1365-2141.2001.02775.x}, DOI={10.1046/j.1365-2141.2001.02775.x}, number={3}, journal={British Journal of Haematology}, publisher={Wiley}, author={Shah, Sanjay J. and Taub, Jeffrey W. and Witt, Teah L. and Pollock, Brad H. and Ding, Bee Ching and Moore, Daniel S. and Amylon, Michael and Pullen, Jeanette and Ravindranath, Yaddanapudi and Matherly, Larry H.}, year={2001}, month=jun, pages={746–756} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2023,
        10,
        15
      ]
    ],
    "date-time": "2023-10-15T23:50:59Z",
    "timestamp": 1697413859599
  },
  "reference-count": 47,
  "publisher": "Wiley",
  "issue": "3",
  "license": [
    {
      "start": {
        "date-parts": [
          [
            2002,
            1,
            12
          ]
        ],
        "date-time": "2002-01-12T00:00:00Z",
        "timestamp": 1010793600000
      },
      "content-version": "vor",
      "delay-in-days": 225,
      "URL": "http://onlinelibrary.wiley.com/termsAndConditions#vor"
    }
  ],
  "content-domain": {
    "domain": [
      "onlinelibrary.wiley.com"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2001,
        6
      ]
    ]
  },
  "abstract": "<jats:p>The downstream effects of p15 and p16 gene deletions and loss of transcripts on dihydrofolate reductase (DHFR) were examined in 63 B\u2010precursor (BP) acute lymphoblastic leukaemia (ALL) samples. p15 and/or p16 gene deletions were seen in 6% and 8%, respectively, of BP\u2010ALL samples; however, losses of p15 and/or p16 transcripts were seen in 26 out of 63 (41%) samples. Loss of p15 transcripts (36\u00b75%) exceeded that for p16 (17\u00b75%). For the 26 BP\u2010ALLs that lacked p15 and/or p16 transcripts, only six (23%) exhibited low levels of DHFR by flow cytometry assay with Pt430, a fluorescent anti\u2010folate. Conversely, 18 out of 37 (49%) BP\u2010ALL samples with intact p15 and/or p16 genes and transcripts showed low levels of DHFR (<jats:italic>P</jats:italic>\u2003=\u20030\u00b704). In p15\u2010 and p16\u2010null K562 cells transfected with a tetracycline\u2010inducible p15 cDNA construct, induction of p15 transcripts and protein was accompanied by decreased growth rates, decreased S\u2010phase fraction, decreased retinoblastoma protein phosphorylation, and markedly reduced levels of DHFR transcripts and protein. Collectively, our results suggest that losses of p15 and/or p16 gene expression result in elevated levels of DHFR in BP\u2010ALL in children. However, additional downstream factors undoubtedly also contribute to elevated levels of this enzyme target.</jats:p>",
  "DOI": "10.1046/j.1365-2141.2001.02775.x",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2003,
        3,
        11
      ]
    ],
    "date-time": "2003-03-11T06:34:18Z",
    "timestamp": 1047364458000
  },
  "page": "746-756",
  "update-policy": "http://dx.doi.org/10.1002/crossmark_policy",
  "source": "Crossref",
  "is-referenced-by-count": 5,
  "title": "Relationship of p15 and p16 gene alterations to elevated dihydrofolate reductase in childhood acute lymphoblastic leukaemia",
  "prefix": "10.1111",
  "volume": "113",
  "author": [
    {
      "given": "Sanjay J.",
      "family": "Shah",
      "sequence": "first",
      "affiliation": []
    },
    {
      "given": "Jeffrey W.",
      "family": "Taub",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Teah L.",
      "family": "Witt",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Brad H.",
      "family": "Pollock",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Bee Ching",
      "family": "Ding",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Daniel S.",
      "family": "Moore",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Michael",
      "family": "Amylon",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Jeanette",
      "family": "Pullen",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Yaddanapudi",
      "family": "Ravindranath",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Larry H.",
      "family": "Matherly",
      "sequence": "additional",
      "affiliation": []
    }
  ],
  "member": "311",
  "published-online": {
    "date-parts": [
      [
        2002,
        1,
        12
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_2_6_2_1",
      "first-page": "832",
      "article-title": "Frequent and selective methylation of p15 and deletion of both p15 and p16 in T\u2010cell acute lymphoblastic leukemia",
      "volume": "57",
      "author": "Batova A.",
      "year": "1997",
      "journal-title": "Cancer Research"
    },
    {
      "key": "e_1_2_6_3_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/978-3-642-84895-7_23"
    },
    {
      "key": "e_1_2_6_4_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V82.9.2617.2617"
    },
    {
      "key": "e_1_2_6_5_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.59.3.766"
    },
    {
      "key": "e_1_2_6_6_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0145-2126(97)00007-6"
    },
    {
      "key": "e_1_2_6_7_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.leu.2401043"
    },
    {
      "key": "e_1_2_6_8_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1056/NEJM194806032382301"
    },
    {
      "key": "e_1_2_6_9_1",
      "doi-asserted-by": "crossref",
      "first-page": "1890",
      "DOI": "10.1016/S0021-9258(19)68121-4",
      "article-title": "Rapid formation of polyglutamyl derivatives of methotrexate and their association with dihydrofolate reductase as assessed by high pressure liquid chromatography in the Ehrlich ascites tumor cells",
      "volume": "257",
      "author": "Fry D.W.",
      "year": "1982",
      "journal-title": "Journal of Biological Chemistry"
    },
    {
      "key": "e_1_2_6_10_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V86.2.677.bloodjournal862677"
    },
    {
      "key": "e_1_2_6_11_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0163-7258(85)90083-X"
    },
    {
      "key": "e_1_2_6_12_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1056/NEJM199610033351408"
    },
    {
      "key": "e_1_2_6_13_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/371257a0"
    },
    {
      "key": "e_1_2_6_14_1",
      "first-page": "837",
      "article-title": "Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies",
      "volume": "57",
      "author": "Herman J.G.",
      "year": "1997",
      "journal-title": "Cancer Research"
    },
    {
      "key": "e_1_2_6_15_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V86.3.841.841"
    },
    {
      "key": "e_1_2_6_16_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/jnci/88.18.1269"
    },
    {
      "key": "e_1_2_6_17_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.8153634"
    },
    {
      "key": "e_1_2_6_18_1",
      "doi-asserted-by": "crossref",
      "first-page": "4161",
      "DOI": "10.1182/blood.V89.11.4161",
      "article-title": "Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome",
      "volume": "89",
      "author": "Kees U.",
      "year": "1997",
      "journal-title": "Blood"
    },
    {
      "key": "e_1_2_6_19_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V90.11.4243"
    },
    {
      "key": "e_1_2_6_20_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1200/JCO.1994.12.9.1939"
    },
    {
      "key": "e_1_2_6_21_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.92.22.10436"
    },
    {
      "key": "e_1_2_6_22_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/MCB.16.3.1047"
    },
    {
      "key": "e_1_2_6_23_1",
      "doi-asserted-by": "crossref",
      "first-page": "2380",
      "DOI": "10.1182/blood.V93.7.2380",
      "article-title": "Acquisition of p16INK4A and p15INK4B gene abnormalities between initial diagnosis and relapse in children with acute lymphoblastic leukemia",
      "volume": "93",
      "author": "Maloney K.W.",
      "year": "1999",
      "journal-title": "Blood"
    },
    {
      "key": "e_1_2_6_24_1",
      "volume-title": "Principles and Practice of Pediatric Oncology",
      "author": "Margolin J.F.",
      "year": "1997"
    },
    {
      "key": "e_1_2_6_25_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.3109/10428199609093433"
    },
    {
      "key": "e_1_2_6_26_1",
      "first-page": "3420",
      "article-title": "Identification of a highly glycosylated methotrexate membrane carrier in K562 human erythroleukemia cells up\u2010regulated for tetrahydrofolate cofactor and methotrexate transport",
      "volume": "51",
      "author": "Matherly L.H.",
      "year": "1991",
      "journal-title": "Cancer Research"
    },
    {
      "key": "e_1_2_6_27_1",
      "doi-asserted-by": "crossref",
      "first-page": "500",
      "DOI": "10.1182/blood.V85.2.500.500",
      "article-title": "Elevated dihydrofolate reductase and impaired methotrexate transport as elements in methotrexate resistance in childhood acute lymphocytic leukemia",
      "volume": "85",
      "author": "Matherly L.H.",
      "year": "1995",
      "journal-title": "Blood"
    },
    {
      "key": "e_1_2_6_28_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V90.2.578"
    },
    {
      "key": "e_1_2_6_29_1",
      "doi-asserted-by": "crossref",
      "first-page": "2321",
      "DOI": "10.1182/blood.V85.9.2321.bloodjournal8592321",
      "article-title": "Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute lymphoblastic leukaemia",
      "volume": "85",
      "author": "Okuda T.",
      "year": "1995",
      "journal-title": "Blood"
    },
    {
      "key": "e_1_2_6_30_1",
      "first-page": "1219",
      "article-title": "Universal inactivation of both p16 and p15 but not downstream components is an essential event in the pathogenesis of T\u2010cell acute lymphoblastic leukemia",
      "volume": "6",
      "author": "Omura\u2010Minamisawa M.",
      "year": "2000",
      "journal-title": "Clinical Cancer Research"
    },
    {
      "key": "e_1_2_6_31_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1056/NEJM199808273390907"
    },
    {
      "key": "e_1_2_6_32_1",
      "doi-asserted-by": "crossref",
      "first-page": "14162",
      "DOI": "10.1016/S0021-9258(19)45359-3",
      "article-title": "A new fluorescent dihydrofolate reductase probe for studies of methotrexate resistance",
      "volume": "257",
      "author": "Rosowsky A.",
      "year": "1982",
      "journal-title": "Journal of Biological Chemistry"
    },
    {
      "key": "e_1_2_6_33_1",
      "unstructured": "SAS Institute(1989)SAS/STAT User's Guide Version 6 4th edn Vol.2.SAS Institute Inc Cary NC."
    },
    {
      "key": "e_1_2_6_34_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1046/j.1365-2141.1996.d01-1753.x"
    },
    {
      "key": "e_1_2_6_35_1",
      "first-page": "3475",
      "article-title": "Activation of the E2F transcription factor by cyclin D1 is blocked by p16INK4, the product of the putative tumor suppressor gene MTS1",
      "volume": "9",
      "author": "Schulze A.",
      "year": "1994",
      "journal-title": "Oncogene"
    },
    {
      "key": "e_1_2_6_36_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/366704a0"
    },
    {
      "key": "e_1_2_6_37_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.274.5293.1672"
    },
    {
      "key": "e_1_2_6_38_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1200/JCO.1996.14.1.18"
    },
    {
      "key": "e_1_2_6_39_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/emboj/17.17.5001"
    },
    {
      "key": "e_1_2_6_40_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/bbrc.1997.6654"
    },
    {
      "key": "e_1_2_6_41_1",
      "doi-asserted-by": "crossref",
      "first-page": "755",
      "DOI": "10.1182/blood.V86.2.755.bloodjournal862755",
      "article-title": "Analysis of a family of cyclin\u2010dependent kinase inhibitors: p15/MTS2/INK4B,p16 /MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood",
      "volume": "86",
      "author": "Takeuchi S.",
      "year": "1995",
      "journal-title": "Blood"
    },
    {
      "key": "e_1_2_6_42_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.leu.2401557"
    },
    {
      "key": "e_1_2_6_43_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/(SICI)1097-0215(19971021)74:5<508::AID-IJC5>3.0.CO;2-7"
    },
    {
      "key": "e_1_2_6_44_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.270.29.17468"
    },
    {
      "key": "e_1_2_6_45_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0006-2952(96)00710-1"
    },
    {
      "key": "e_1_2_6_46_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0006-2952(97)00639-4"
    },
    {
      "key": "e_1_2_6_47_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1172/JCI116435"
    },
    {
      "key": "e_1_2_6_48_1",
      "first-page": "2169",
      "article-title": "Reduced folate carrier gene expression in childhood acute lymphoblastic leukemia: relationship to immunophenotype and ploidy",
      "volume": "4",
      "author": "Zhang L.",
      "year": "1998",
      "journal-title": "Clinical Cancer Research"
    }
  ],
  "container-title": "British Journal of Haematology",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1046%2Fj.1365-2141.2001.02775.x",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "text-mining"
    },
    {
      "URL": "https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1046%2Fj.1365-2141.2001.02775.x",
      "content-type": "application/pdf",
      "content-version": "vor",
      "intended-application": "text-mining"
    },
    {
      "URL": "https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2141.2001.02775.x",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2023,
        9,
        27
      ]
    ],
    "date-time": "2023-09-27T15:13:01Z",
    "timestamp": 1695827581000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2001.02775.x"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2001,
        6
      ]
    ]
  },
  "references-count": 47,
  "journal-issue": {
    "issue": "3",
    "published-print": {
      "date-parts": [
        [
          2001,
          6
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1046/j.1365-2141.2001.02775.x"
  ],
  "URL": "http://dx.doi.org/10.1046/j.1365-2141.2001.02775.x",
  "relation": {},
  "ISSN": [
    "0007-1048",
    "1365-2141"
  ],
  "subject": [],
  "container-title-short": "Br J Haematol",
  "published": {
    "date-parts": [
      [
        2001,
        6
      ]
    ]
  },
  "assertion": [
    {
      "value": "2002-01-12",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}