Grb10 is involved in BCR-ABL-positive leukemia in mice
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Grb10 is involved in BCR-ABL-positive leukemia in mice. / Illert, A L; Albers, C; Kreutmair, S; Leischner, H; Peschel, C; Miething, C; Duyster, J.
In: LEUKEMIA, Vol. 29, No. 4, 04.2015, p. 858-68.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Grb10 is involved in BCR-ABL-positive leukemia in mice
AU - Illert, A L
AU - Albers, C
AU - Kreutmair, S
AU - Leischner, H
AU - Peschel, C
AU - Miething, C
AU - Duyster, J
PY - 2015/4
Y1 - 2015/4
N2 - The SH2-containing adaptor protein Grb10 was first identified in a yeast screen as a new binding partner for BCR-ABL and associates with BCR-ABL in a tyrosine-dependent manner. However, its function in BCR-ABL-mediated leukemogenesis in vivo is still unknown. Here we describe an important role of Grb10 in BCR-ABL-induced leukemia by using a versatile system for efficient oncogene expression and simultaneous Grb10 knockdown from a single vector. Primary bone marrow (BM) cells coexpressing Grb10-miR/BCR-ABL showed a significant decrease in colony formation and cell cycle progression. Transplantation of Grb10miR/BCR-ABL- or control-miR/BCR-ABL- transduced BM leads to a CML/B-ALL-like phenotype with significantly delayed disease onset and progression resulting in prolonged overall survival in Grb10-miR-transplanted mice. Methylcellulose experiments exhibit additive effects of imatinib treatment and Grb10 knockdown. Cell cycle analysis suggests an anti-proliferative effect of Grb10 knockdown in BCR-ABL(+) primary BM cells. However, Grb10 abrogation was not capable of completely abolishing the BCR-ABL-induced disease. Our findings were confirmed in the human BCR-ABL(+) cell line K562, where we demonstrate reduced viability, cell cycle progression and induction of apoptosis by stable Grb10 microRNA expression. Taken together, our results suggest that Grb10 knockdown in vivo leads to impaired proliferation, longer survival and reduced colony formation, suggesting an important role of Grb10 in BCR-ABL-mediated leukemogenesis.
AB - The SH2-containing adaptor protein Grb10 was first identified in a yeast screen as a new binding partner for BCR-ABL and associates with BCR-ABL in a tyrosine-dependent manner. However, its function in BCR-ABL-mediated leukemogenesis in vivo is still unknown. Here we describe an important role of Grb10 in BCR-ABL-induced leukemia by using a versatile system for efficient oncogene expression and simultaneous Grb10 knockdown from a single vector. Primary bone marrow (BM) cells coexpressing Grb10-miR/BCR-ABL showed a significant decrease in colony formation and cell cycle progression. Transplantation of Grb10miR/BCR-ABL- or control-miR/BCR-ABL- transduced BM leads to a CML/B-ALL-like phenotype with significantly delayed disease onset and progression resulting in prolonged overall survival in Grb10-miR-transplanted mice. Methylcellulose experiments exhibit additive effects of imatinib treatment and Grb10 knockdown. Cell cycle analysis suggests an anti-proliferative effect of Grb10 knockdown in BCR-ABL(+) primary BM cells. However, Grb10 abrogation was not capable of completely abolishing the BCR-ABL-induced disease. Our findings were confirmed in the human BCR-ABL(+) cell line K562, where we demonstrate reduced viability, cell cycle progression and induction of apoptosis by stable Grb10 microRNA expression. Taken together, our results suggest that Grb10 knockdown in vivo leads to impaired proliferation, longer survival and reduced colony formation, suggesting an important role of Grb10 in BCR-ABL-mediated leukemogenesis.
KW - Animals
KW - Antineoplastic Agents
KW - Apoptosis
KW - Benzamides
KW - Bone Marrow Cells
KW - Cell Cycle
KW - Cell Proliferation
KW - Disease Models, Animal
KW - Female
KW - Fusion Proteins, bcr-abl
KW - GRB10 Adaptor Protein
KW - Gene Expression Regulation, Leukemic
KW - Humans
KW - Imatinib Mesylate
KW - K562 Cells
KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive
KW - Mice
KW - Mice, Inbred BALB C
KW - MicroRNAs
KW - Piperazines
KW - Primary Cell Culture
KW - Pyrimidines
KW - RNA, Small Interfering
KW - Signal Transduction
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/leu.2014.283
DO - 10.1038/leu.2014.283
M3 - SCORING: Journal article
C2 - 25249015
VL - 29
SP - 858
EP - 868
JO - LEUKEMIA
JF - LEUKEMIA
SN - 0887-6924
IS - 4
ER -