Suppression of malignant rhabdoid tumors through Chb-M'-mediated RUNX1 inhibition.

Published on Feb 1, 2021in Pediatric Blood & Cancer2.355
· DOI :10.1002/PBC.28789
Tomoo Daifu2
Estimated H-index: 2
(Kyoto University),
Masamitsu Mikami4
Estimated H-index: 4
(Kyoto University)
+ 20 AuthorsYasuhiko Kamikubo14
Estimated H-index: 14
(Kyoto University)
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.
📖 Papers frequently viewed together
35 Citations
7 Citations
3 Citations
#1Yasuhiko Kamikubo (Kyoto University)H-Index: 14
: Runt (Runt domain)-related transcription factor 1 (RUNX1) is a transcription factor belonging to the core-binding factor (CBF) family. It is considered to be a master regulator of hematopoiesis and has been regarded as a tumor suppressor because it is essential for definitive hematopoiesis in vertebrates. It is one of the most frequent target genes of chromosomal translocation in leukemia, and germ line mutation of RUNX1 causes familial platelet disorder with associated myeloid malignancies. S...
8 CitationsSource
#1Yoshihide Mitsuda (Kyoto University)H-Index: 2
#2Ken Morita (Kyoto University)H-Index: 8
Last. Yasuhiko Kamikubo (Kyoto University)H-Index: 14
view all 15 authors...
The dual function of runt-related transcriptional factor 1 (RUNX1) as an oncogene or oncosuppressor has been extensively studied in various malignancies, yet its role in gastric cancer remains elusive. Up-regulation of the ErbB2/HER2 signaling pathway is frequently-encountered in gastric cancer and contributes to the maintenance of these cancer cells. This signaling cascade is partly mediated by son of sevenless homolog (SOS) family, which function as adaptor proteins in the RTK cascades. Herein...
16 CitationsSource
#1Ken MoritaH-Index: 8
#2Chieko TokushigeH-Index: 3
Last. Yasuhiko KamikuboH-Index: 14
view all 16 authors...
Although the function of Runt-related (RUNX) transcription factors has been well characterized in leukemogenesis and regarded as an ideal target in antileukemia strategies, the effect of RUNX-inhibition therapy on bone marrow niche cells andr its impact on the engraftment of acute myeloid leukemia (AML) cells have largely been unknown. Here, we provide evidence suggesting the possible involvement of RUNX transcription factors in the transactivation of E-selectin , a member of selectin family of ...
8 CitationsSource
#1Ken Morita (Kyoto University)H-Index: 8
#2Mina Noura (Kyoto University)H-Index: 4
Last. Yasuhiko Kamikubo (Kyoto University)H-Index: 14
view all 17 authors...
Although runt-related transcription factor 1 (RUNX1) and its associating core binding factor-β (CBFB) play pivotal roles in leukemogenesis, and inhibition of RUNX1 has now been widely recognized as a novel strategy for anti-leukemic therapies, it has been elusive how leukemic cells could acquire the serious resistance against RUNX1-inhibition therapies and also whether CBFB could participate in this process. Here, we show evidence that p53 (TP53) and CBFB are sequentially up-regulated in respons...
9 CitationsSource
#1Ken MoritaH-Index: 8
#2Kensho SuzukiH-Index: 2
Last. Yasuhiko KamikuboH-Index: 14
view all 29 authors...
: Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia, but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML). Here we have demonstrated that the antileukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway. Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the anti...
53 CitationsSource
#1Raman Sood (NIH: National Institutes of Health)H-Index: 36
#2Yasuhiko Kamikubo (Kyoto University)H-Index: 14
Last. Paul Liu (NIH: National Institutes of Health)H-Index: 29
view all 3 authors...
RUNX1 is a member of the core binding factor family of transcription factors and is indispensable for the establishment of definitive hematopoiesis in vertebrates. RUNX1 is one of the most frequently mutated genes in a variety of hematological malignancies. Germline mutations in RUNX1 cause familial platelet disorder with associated myeloid malignancies (FPDMM). Somatic mutations and chromosomal rearrangements involving RUNX1 are frequently observed in myelodysplastic syndrome (MDS) and leukemia...
158 CitationsSource
#1Deli Hong (UVM: University of Vermont)H-Index: 14
#2Terri L. Messier (UVM: University of Vermont)H-Index: 16
Last. Gary S. Stein (UVM: University of Vermont)H-Index: 133
view all 10 authors...
// Deli Hong 1, 2 , Terri L. Messier 1 , Coralee E. Tye 1 , Jason R. Dobson 2 , Andrew J. Fritz 1 , Kenneth R. Sikora 1 , Gillian Browne 1 , Janet L. Stein 1 , Jane B. Lian 1 , Gary S. Stein 1 1 Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA 2 Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA Correspondence to: Gary S. Stein, email: Key...
29 CitationsSource
#1Ken MoritaH-Index: 8
#2Shintaro MaedaH-Index: 4
Last. Yasuhiko KamikuboH-Index: 14
view all 9 authors...
Although Runt-related transcription factor 1 (RUNX1), a member of RUNX transcription family, is known for its oncogenic role in the development of acute myeloid leukemia (AML), evidence from other groups support the oncosuppressive property of RUNX1 in leukemia cells, casting a question over the bidirectional function of RUNX1 and it is currently highly controversial. Here we report that the dual function of RUNX1 possibly arise from the total level of RUNX family expressions. To examine the pre...
6 CitationsSource
#1Bernadette Brennan (Boston Children's Hospital)H-Index: 25
#2Gian Luca De SalvoH-Index: 27
Last. Andrea FerrariH-Index: 63
view all 11 authors...
Abstract Background Extracranial malignant rhabdoid tumours (MRT) are rare lethal childhood cancers that often occur in infants and have a characteristic genetic mutation in the SMARCB1 gene. The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) conducted a multinational prospective study of registered cases of extracranial MRT to test an intensive multimodal approach of treatment for children with newly diagnosed extracranial MRT. Methods Between December 2005 and June 2014, we prospe...
27 CitationsSource
#1Bernadette Brennan (Boston Children's Hospital)H-Index: 25
#2Charles A. StillerH-Index: 81
Last. Franck Bourdeaut (Curie Institute)H-Index: 33
view all 3 authors...
Summary Extracranial rhabdoid tumours are rare, and often occur in infants. Although the kidney is the most common site, they can occur anywhere in the body. Most contain a biallelic inactivating mutation in SMARCB1 , which is part of the chromatin remodelling complex SWI/SNF, and functions as a classic tumour suppressor gene. Despite multimodal therapy, outcome in rhabdoid tumours remains poor with only 31% of patients surviving to 1 year. The young age of patients limits use of radiotherapy, w...
50 CitationsSource
Cited By0