Chd7 deficiency delays leukemogenesis in mice induced by Cbfb-MYH11

Tao Zhen, Erika M. Kwon, Ling Zhao, Jingmei Hsu, Ricia K Hyde, Ying Lu, Lemlem Alemu, Nancy A. Speck, P. Paul Liu

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia, which generates a CBFB-MYH11 fusion gene. Previous studies showed that the interaction between CBFb-smooth muscle myosin heavy chain (SMMHC; encoded by CBFB-MYH11) and RUNX1 plays a critical role in the pathogenesis of this leukemia. Recently, it was shown that chromodomain helicase DNA-binding protein-7 (CHD7) interacts with RUNX1 and suppresses RUNX1-induced expansion of hematopoietic stem and progenitor cells. These results suggest that CHD7 is also critical for CBFB-MYH11–induced leukemogenesis. To test this hypothesis, we generated Chd7f/fMx1-CreCbfb1/56M mice, which expressed the Cbfb-MYH11 fusion gene and deactivated Chd7 in hematopoietic cells upon inducing Cre with polyinosinic-polycytidylic acid. The LinSca1c-Kit1 (LK) population was significantly lower in Chd7f/fMx1-CreCbfb1/56M mice than in Mx1-CreCbfb1/56M mice. In addition, there were fewer 5-bromo-29-deoxyuridine–positive cells in the LK population in Chd7f/fMx1-CreCbfb1/56M mice, and genes associated with cell cycle, cell growth, and proliferation were differentially expressed between Chd7f/fMx1-CreCbfb1/56M and Mx1-CreCbfb1/56M leukemic cells. In vitro studies showed that CHD7 interacted with CBFb-SMMHC through RUNX1 and that CHD7 enhanced transcriptional activity of RUNX1 and CBFb-SMMHC on Csf1r, a RUNX1 target gene. Moreover, RNA sequencing of c-Kit1 cells showed that CHD7 functions mostly through altering the expression of RUNX1 target genes. Most importantly, Chd7 deficiency delayed Cbfb-MYH11– induced leukemia in both primary and transplanted mice. These data indicate that Chd7 is important for Cbfb-MYH11– induced leukemogenesis by facilitating RUNX1 regulation of transcription and cellular proliferation.

Original languageEnglish (US)
Pages (from-to)2431-2442
Number of pages12
JournalBlood
Volume130
Issue number22
DOIs
StatePublished - Nov 30 2017

Fingerprint

DNA-Binding Proteins
Genes
Gene Fusion
Hematopoietic Stem Cells
Leukemia
Fusion reactions
Cell Proliferation
Leukemia, Myelomonocytic, Acute
Smooth Muscle Myosins
RNA Sequence Analysis
Chromosomes, Human, Pair 16
Poly I-C
Myosin Heavy Chains
Cell proliferation
Eosinophilia
Cell growth
Transcription
Chromosomes
Population
Cell Cycle

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Zhen, T., Kwon, E. M., Zhao, L., Hsu, J., Hyde, R. K., Lu, Y., ... Liu, P. P. (2017). Chd7 deficiency delays leukemogenesis in mice induced by Cbfb-MYH11. Blood, 130(22), 2431-2442. https://doi.org/10.1182/blood-2017-04-780106

Chd7 deficiency delays leukemogenesis in mice induced by Cbfb-MYH11. / Zhen, Tao; Kwon, Erika M.; Zhao, Ling; Hsu, Jingmei; Hyde, Ricia K; Lu, Ying; Alemu, Lemlem; Speck, Nancy A.; Liu, P. Paul.

In: Blood, Vol. 130, No. 22, 30.11.2017, p. 2431-2442.

Research output: Contribution to journalArticle

Zhen, T, Kwon, EM, Zhao, L, Hsu, J, Hyde, RK, Lu, Y, Alemu, L, Speck, NA & Liu, PP 2017, 'Chd7 deficiency delays leukemogenesis in mice induced by Cbfb-MYH11', Blood, vol. 130, no. 22, pp. 2431-2442. https://doi.org/10.1182/blood-2017-04-780106
Zhen, Tao ; Kwon, Erika M. ; Zhao, Ling ; Hsu, Jingmei ; Hyde, Ricia K ; Lu, Ying ; Alemu, Lemlem ; Speck, Nancy A. ; Liu, P. Paul. / Chd7 deficiency delays leukemogenesis in mice induced by Cbfb-MYH11. In: Blood. 2017 ; Vol. 130, No. 22. pp. 2431-2442.
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abstract = "Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia, which generates a CBFB-MYH11 fusion gene. Previous studies showed that the interaction between CBFb-smooth muscle myosin heavy chain (SMMHC; encoded by CBFB-MYH11) and RUNX1 plays a critical role in the pathogenesis of this leukemia. Recently, it was shown that chromodomain helicase DNA-binding protein-7 (CHD7) interacts with RUNX1 and suppresses RUNX1-induced expansion of hematopoietic stem and progenitor cells. These results suggest that CHD7 is also critical for CBFB-MYH11–induced leukemogenesis. To test this hypothesis, we generated Chd7f/fMx1-CreCbfb1/56M mice, which expressed the Cbfb-MYH11 fusion gene and deactivated Chd7 in hematopoietic cells upon inducing Cre with polyinosinic-polycytidylic acid. The Lin–Sca1–c-Kit1 (LK) population was significantly lower in Chd7f/fMx1-CreCbfb1/56M mice than in Mx1-CreCbfb1/56M mice. In addition, there were fewer 5-bromo-29-deoxyuridine–positive cells in the LK population in Chd7f/fMx1-CreCbfb1/56M mice, and genes associated with cell cycle, cell growth, and proliferation were differentially expressed between Chd7f/fMx1-CreCbfb1/56M and Mx1-CreCbfb1/56M leukemic cells. In vitro studies showed that CHD7 interacted with CBFb-SMMHC through RUNX1 and that CHD7 enhanced transcriptional activity of RUNX1 and CBFb-SMMHC on Csf1r, a RUNX1 target gene. Moreover, RNA sequencing of c-Kit1 cells showed that CHD7 functions mostly through altering the expression of RUNX1 target genes. Most importantly, Chd7 deficiency delayed Cbfb-MYH11– induced leukemia in both primary and transplanted mice. These data indicate that Chd7 is important for Cbfb-MYH11– induced leukemogenesis by facilitating RUNX1 regulation of transcription and cellular proliferation.",
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AU - Zhen, Tao

AU - Kwon, Erika M.

AU - Zhao, Ling

AU - Hsu, Jingmei

AU - Hyde, Ricia K

AU - Lu, Ying

AU - Alemu, Lemlem

AU - Speck, Nancy A.

AU - Liu, P. Paul

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N2 - Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia, which generates a CBFB-MYH11 fusion gene. Previous studies showed that the interaction between CBFb-smooth muscle myosin heavy chain (SMMHC; encoded by CBFB-MYH11) and RUNX1 plays a critical role in the pathogenesis of this leukemia. Recently, it was shown that chromodomain helicase DNA-binding protein-7 (CHD7) interacts with RUNX1 and suppresses RUNX1-induced expansion of hematopoietic stem and progenitor cells. These results suggest that CHD7 is also critical for CBFB-MYH11–induced leukemogenesis. To test this hypothesis, we generated Chd7f/fMx1-CreCbfb1/56M mice, which expressed the Cbfb-MYH11 fusion gene and deactivated Chd7 in hematopoietic cells upon inducing Cre with polyinosinic-polycytidylic acid. The Lin–Sca1–c-Kit1 (LK) population was significantly lower in Chd7f/fMx1-CreCbfb1/56M mice than in Mx1-CreCbfb1/56M mice. In addition, there were fewer 5-bromo-29-deoxyuridine–positive cells in the LK population in Chd7f/fMx1-CreCbfb1/56M mice, and genes associated with cell cycle, cell growth, and proliferation were differentially expressed between Chd7f/fMx1-CreCbfb1/56M and Mx1-CreCbfb1/56M leukemic cells. In vitro studies showed that CHD7 interacted with CBFb-SMMHC through RUNX1 and that CHD7 enhanced transcriptional activity of RUNX1 and CBFb-SMMHC on Csf1r, a RUNX1 target gene. Moreover, RNA sequencing of c-Kit1 cells showed that CHD7 functions mostly through altering the expression of RUNX1 target genes. Most importantly, Chd7 deficiency delayed Cbfb-MYH11– induced leukemia in both primary and transplanted mice. These data indicate that Chd7 is important for Cbfb-MYH11– induced leukemogenesis by facilitating RUNX1 regulation of transcription and cellular proliferation.

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