TY - JOUR
T1 - Malignant transformation of Slp65-deficient pre-B cells involves disruption of the Arf-Mdm2-p53 tumor suppressor pathway
AU - Ta, V. B.T.
AU - De Bruijn, Marjolein J.W.
AU - Ter Brugge, Petra J.
AU - Van Hamburg, Jan Piet
AU - Diepstraten, Hans J.A.
AU - Van Loo, Pieter Fokko
AU - Kersseboom, Rogier
AU - Hendriks, Rudi W.
PY - 2010/2/18
Y1 - 2010/2/18
N2 - The adapter protein Slp65 is a key component of the precursor-B (pre-B) cell receptor. Slp65-deficient mice spontaneously develop pre-B cell leukemia, but the mechanism by which Slp65-/- pre-B cells become malignant is unknown. Loss of Btk, a Tec-family kinase that cooperates with Slp65 as a tumor suppressor, synergizes with deregulation of the c-Myc oncogene during lymphoma formation. Here, we report that the presence of the immunoglobulin heavy chain transgene VH81X prevented tumor development in Btk -/-Slp65-/- mice. This finding paralleled the reported effect of a human immunoglobulin heavy chain transgene on lymphoma development in Eμ-myc mice, expressing transgenic c-Myc. Because activation of c-Myc strongly selects for spontaneous inactivation of the p19Arf-Mdm2-p53 tumor suppressor pathway, we investigated whether disruption of this pathway is a common alteration in Slp65-/- pre-B cell tumors. We found that combined loss of Slp65 and p53 in mice transformed pre-B cells very efficiently. Aberrations in p19Arf, Mdm2, or p53 expression were found in all Slp65-/-(n = 17)andBtk-/-Slp65-/-(n = 32) pre-B cell leukemias analyzed. In addition, 9 of 10 p53-/-Slp65 -/- pre-B cell leukemias manifested significant Mdm2 protein expression. These data indicate that malignant transformation of Slp65 -/- pre-B cells involves disruption of the p19Arf-Mdm2-p53 tumor suppressor pathway.
AB - The adapter protein Slp65 is a key component of the precursor-B (pre-B) cell receptor. Slp65-deficient mice spontaneously develop pre-B cell leukemia, but the mechanism by which Slp65-/- pre-B cells become malignant is unknown. Loss of Btk, a Tec-family kinase that cooperates with Slp65 as a tumor suppressor, synergizes with deregulation of the c-Myc oncogene during lymphoma formation. Here, we report that the presence of the immunoglobulin heavy chain transgene VH81X prevented tumor development in Btk -/-Slp65-/- mice. This finding paralleled the reported effect of a human immunoglobulin heavy chain transgene on lymphoma development in Eμ-myc mice, expressing transgenic c-Myc. Because activation of c-Myc strongly selects for spontaneous inactivation of the p19Arf-Mdm2-p53 tumor suppressor pathway, we investigated whether disruption of this pathway is a common alteration in Slp65-/- pre-B cell tumors. We found that combined loss of Slp65 and p53 in mice transformed pre-B cells very efficiently. Aberrations in p19Arf, Mdm2, or p53 expression were found in all Slp65-/-(n = 17)andBtk-/-Slp65-/-(n = 32) pre-B cell leukemias analyzed. In addition, 9 of 10 p53-/-Slp65 -/- pre-B cell leukemias manifested significant Mdm2 protein expression. These data indicate that malignant transformation of Slp65 -/- pre-B cells involves disruption of the p19Arf-Mdm2-p53 tumor suppressor pathway.
UR - http://www.scopus.com/inward/record.url?scp=77949898410&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/blood-2009-05-222166
DO - https://doi.org/10.1182/blood-2009-05-222166
M3 - Article
C2 - 20008789
SN - 0006-4971
VL - 115
SP - 1385
EP - 1393
JO - Blood
JF - Blood
IS - 7
ER -