Accelerated Leukemogenesis by Truncated CBFβ-SMMHC Defective in High-Affinity Binding with RUNX1

Kamikubo, Yasuhiko; Zhao, Ling; Wunderlich, Mark; Corpora, Takeshi; Hyde, R. Katherine; Paul, Thomas A.; Kundu, Mondira; Garrett, Lisa; Compton, Sheila; Huang, Gang; Wolff, Linda; Ito, Yoshiaki; Bushweller, John H.; Mulloy, James C.; Liu, P. Paul

doi:10.1016/j.ccr.2010.03.022

Cited by 41 publications

(57 citation statements)

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“…Excluding microarray analysis, statistical significance was assessed using the student t test by Excel (Microsoft). Transplantation experiments were performed as described, 16 with injection of 10 6 or 10 7 cells The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734.…”

Section: Methodsmentioning

confidence: 99%

“…3,10,16 The mouse studies were approved by the National Human Genome Research Institute Animal Care and Use Committee, and followed relevant National Institutes of Health and national guidelines and regulations. Western blot analysis using antibodies against CBF␤ and tubulin were performed as previously described.…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis using antibodies against CBF␤ and tubulin were performed as previously described. 4,16,17 Flow cytometry analysis and histologic analysis were conducted as previously described. 4,16 Colony forming assays were performed as previously described.…”

Section: Methodsmentioning

confidence: 99%

“…4,16,17 Flow cytometry analysis and histologic analysis were conducted as previously described. 4,16 Colony forming assays were performed as previously described. 4,16 The MCSFR reporter assay was performed as described before except that the cells were transfected in 96-well plates.…”

Section: Methodsmentioning

confidence: 99%

“…4,16 The MCSFR reporter assay was performed as described before except that the cells were transfected in 96-well plates. 16,18 The pCMV-CBFB-MYH11⌬C95 plasmid was generated using the EcoRI-NotI fragment from pCBFB-MYH11 ⌬C9511 . For microarray analysis (GSE42238), RNA was prepared from peripheral blood cells of E12.5 embryos, hybridized in triplicate, and analyzed as previously described.…”

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The C-terminus of CBFβ-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis

Kamikubo¹,

Hyde²,

Zhao³

et al. 2013

Blood

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• Heterozygous CBF␤-SMMHC⌬C95 knock-in mice have normal hematopoiesis.• Heterozygous CBF␤-SMMHC⌬C95 knock-in mice do not develop leukemia.The C-terminus of CBF␤-SMMHC, the fusion protein produced by a chromosome 16 inversion in acute myeloid leukemia subtype M4Eo, contains domains for selfmultimerization and transcriptional repression, both of which have been proposed to be important for leukemogenesis by CBF␤-SMMHC. To test the role of the fusion protein's C-terminus in vivo, we generated knock-in mice expressing a C-terminally truncated CBF␤-SMMHC (CBF␤-SMMHC⌬C95). Embryos with a single copy of CBF␤-SMMHC⌬C95 were viable and showed no defects in hematopoiesis, whereas embryos homozygous for the CBF␤-SMMHC⌬C95 allele had hematopoietic defects and died in mid-gestation, similar to embryos with a single-copy of the full-length CBF␤-SMMHC. Importantly, unlike mice expressing full-length CBF␤-SMMHC, none of the mice expressing CBF␤-SMMHC⌬C95 developed leukemia, even after treatment with a mutagen, although some of the older mice developed a nontransplantable myeloproliferative disease. Our data indicate that the CBF␤-SMMHC's C-terminus is essential to induce embryonic hematopoietic defects and leukemogenesis. (Blood. 2013;121(4):638-642) IntroductionInversion 16 (Inv16) results in the fusion of the transcription factor gene, CBFB, and MYH11, which encodes smooth muscle myosin heavy chain (SMMHC). 1 Expression of CBF␤-SMMHC is probably the initiating event in Inv16 AML 2 ; however, its mechanism is not well understood.Previously, we generated knock-in mice expressing Cbfb-MYH11 3 to address the role of the fusion gene in vivo. Mice expressing a single allele of the fusion gene (Cbfb ϩ/MYH11 ) showed defective primitive hematopoiesis, blocked definitive hematopoiesis, and embryonic lethality. 3,4 Interestingly, except for the primitive hematopoietic defect, this phenotype is indistinguishable from mice lacking functional Cbfb 5-7 or its dimerization partner Runx1, 8,9 implying that Cbfb-MYH11 has dominant negative activities. Importantly, nearly 100% of the Cbfb-MYH11 mice develop AML within 6 months after treatment with a mutagen. 2,10 This demonstrates that expression of Cbfb-MYH11 is necessary, but not sufficient for AML.The C-terminus of CBF␤-SMMHC consists of repeated ␣-helical rod domains that facilitate self-dimerization and multimerization. [11][12][13] Work in myeloid cells indicates CBF␤-SMMHC's ability to form multimers correlates with its ability to repress proliferation and transcription. 12,13 In addition, CBF␤-SMMHC C-terminus can interact with transcriptional corepressors, 14,15 providing a possible mechanism for its dominant negative effects on transcriptional regulation by CBF␤/RUNX1. CBF␤-SMMHC multimerization and transcriptional repression are potential mechanisms for leukemogenesis, implying that the C-terminal region is critically important. To test the requirement of this region in vivo, we generated knock-in mice expressing a truncated Cbfb-MYH11 that encodes a CBF␤-SMMHC fusion protein missin...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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The C-terminus of CBFβ-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis

Kamikubo¹,

Hyde²,

Zhao³

et al. 2013

Blood

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RUNX1 repression‐independent mechanisms of leukemogenesis by fusion genes CBFB–MYH11 and AML1–ETO (RUNX1–RUNX1T1)

Hyde

Liu

2010

J of Cellular Biochemistry

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SUMMARY The Core Binding Factor (CBF) acute myeloid leukemias (AMLs) are a prognostically distinct subgroup that includes patients with the inv(16) and t(8:21) chromosomal rearrangements. Both of these rearrangements result in the formation of fusion proteins, CBFB-MYH11 and AML1-ETO respectively, that involve members of the CBF family of transcription factors. It has been proposed that both of these fusion proteins function primarily by dominantly repressing normal CBF transcription. However, recent reports have indicted that additional, CBF-repression independent activities may be equally important during leukemogenesis. This article will focus on these recent advances.

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Suppression of malignant rhabdoid tumors through Chb‐M′‐mediated RUNX1 inhibition

Daifu

Mikami

Hiramatsu

et al. 2020

Pediatric Blood & Cancer

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Malignant rhabdoid tumor (MRT) is a rare and highly aggressive pediatric malignancy primarily affecting infants and young children. Intensive multimodal therapies currently given to MRT patients are not sufficiently potent to control this highly malignant tumor. Therefore, additive or alternative therapy for these patients with a poor prognosis is necessary. We herein demonstrated that the inhibition of runt-related transcription factor 1 (RUNX1) by novel alkylating conjugated pyrrole-imidazole (PI) polyamides, which specifically recognize and bind to RUNX-binding DNA sequences, was highly effective in the treatment of rhabdoid tumor cell lines in vitro as well as in an in vivo mouse model. Therefore, suppression of RUNX1 activity may be a novel strategy for MRT therapy. K E Y W O R D S malignant rhabdoid tumor, p53, polyamide, RUNX1 1 BACKGROUND Malignant rhabdoid tumor (MRT) is a rare and highly aggressive malignancy, which affects infants and young children. 1 MRT occurs at various anatomical locations including the kidneys, central nervous system (CNS), liver, heart, mediastinum, uterus, adnexa, urinary blad-Abbreviations: Chb-M′, chlorambucil-M prime; MRT, malignant rhabdoid tumor der, and soft tissue. Despite the existing standard intensive multimodal therapy, the long-term survival rate of MRT patients is less than 30%. 2,3 Therefore, more effective treatments are highly desired. The genetic hallmark of rhabdoid tumors are mutations of SMARCB1 (INI1), a core subunit of the SWI/SNF chromatin-remodeling complex. SMARCB1 has potent tumor suppressor activity, and Wang et al reported that oncogenesis caused by loss of SMARCB1 might be dependent on the activity of the residual SWI/SNF

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Accelerated Leukemogenesis by Truncated CBFβ-SMMHC Defective in High-Affinity Binding with RUNX1

Cited by 41 publications

References 49 publications

The C-terminus of CBFβ-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis

The C-terminus of CBFβ-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis

RUNX1 repression‐independent mechanisms of leukemogenesis by fusion genes CBFB–MYH11 and AML1–ETO (RUNX1–RUNX1T1)

Suppression of malignant rhabdoid tumors through Chb‐M′‐mediated RUNX1 inhibition

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