A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome

Jillian L. Barlow, Lesley F. Drynan, Duncan Hewett, Luke R. Holmes, Silvia Lorenzo-Abalde, Alison L. Lane, Helen E. Jolin, Richard Pannell, Angela J. Middleton, See Heng Wong, Alan J. Warren, James S. Wainscoat, Jacqueline Boultwood, Andrew N.J. McKenzie

Research output: Contribution to journalArticle

246 Citations (Scopus)

Abstract

The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q-syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q-syndrome.

LanguageEnglish
Pages59-66
Number of pages8
JournalNature Medicine
Volume16
Issue number1
DOIs
Publication statusPublished - 1 Jan 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Barlow, J. L., Drynan, L. F., Hewett, D., Holmes, L. R., Lorenzo-Abalde, S., Lane, A. L., ... McKenzie, A. N. J. (2010). A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome. Nature Medicine, 16(1), 59-66. https://doi.org/10.1038/nm.2063
Barlow, Jillian L. ; Drynan, Lesley F. ; Hewett, Duncan ; Holmes, Luke R. ; Lorenzo-Abalde, Silvia ; Lane, Alison L. ; Jolin, Helen E. ; Pannell, Richard ; Middleton, Angela J. ; Wong, See Heng ; Warren, Alan J. ; Wainscoat, James S. ; Boultwood, Jacqueline ; McKenzie, Andrew N.J. / A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome. In: Nature Medicine. 2010 ; Vol. 16, No. 1. pp. 59-66.
@article{4c178060024941f1af7807175549d49d,
title = "A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome",
abstract = "The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q-syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q-syndrome.",
author = "Barlow, {Jillian L.} and Drynan, {Lesley F.} and Duncan Hewett and Holmes, {Luke R.} and Silvia Lorenzo-Abalde and Lane, {Alison L.} and Jolin, {Helen E.} and Richard Pannell and Middleton, {Angela J.} and Wong, {See Heng} and Warren, {Alan J.} and Wainscoat, {James S.} and Jacqueline Boultwood and McKenzie, {Andrew N.J.}",
year = "2010",
month = "1",
day = "1",
doi = "10.1038/nm.2063",
language = "English",
volume = "16",
pages = "59--66",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "1",

}

Barlow, JL, Drynan, LF, Hewett, D, Holmes, LR, Lorenzo-Abalde, S, Lane, AL, Jolin, HE, Pannell, R, Middleton, AJ, Wong, SH, Warren, AJ, Wainscoat, JS, Boultwood, J & McKenzie, ANJ 2010, 'A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome', Nature Medicine, vol. 16, no. 1, pp. 59-66. https://doi.org/10.1038/nm.2063

A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome. / Barlow, Jillian L.; Drynan, Lesley F.; Hewett, Duncan; Holmes, Luke R.; Lorenzo-Abalde, Silvia; Lane, Alison L.; Jolin, Helen E.; Pannell, Richard; Middleton, Angela J.; Wong, See Heng; Warren, Alan J.; Wainscoat, James S.; Boultwood, Jacqueline; McKenzie, Andrew N.J.

In: Nature Medicine, Vol. 16, No. 1, 01.01.2010, p. 59-66.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome

AU - Barlow, Jillian L.

AU - Drynan, Lesley F.

AU - Hewett, Duncan

AU - Holmes, Luke R.

AU - Lorenzo-Abalde, Silvia

AU - Lane, Alison L.

AU - Jolin, Helen E.

AU - Pannell, Richard

AU - Middleton, Angela J.

AU - Wong, See Heng

AU - Warren, Alan J.

AU - Wainscoat, James S.

AU - Boultwood, Jacqueline

AU - McKenzie, Andrew N.J.

PY - 2010/1/1

Y1 - 2010/1/1

N2 - The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q-syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q-syndrome.

AB - The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q-syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q-syndrome.

UR - http://www.scopus.com/inward/record.url?scp=73849128091&partnerID=8YFLogxK

U2 - 10.1038/nm.2063

DO - 10.1038/nm.2063

M3 - Article

VL - 16

SP - 59

EP - 66

JO - Nature Medicine

T2 - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 1

ER -