Congratulations to Desmond Chin, PhD student from A/Prof. Motomi Osato’s group, for winning the Bronze Oral Presentation Award at the 6th JSH International Symposium 2015, an annual symposium organized by the Japanese Society of Hematology from 22-23 May 2015 in Karuizawa, Japan.
The theme for this year’s symposium was “New Era of Bone Marrow Failure, Including MDS and MPN”. The symposium offers an excellent opportunity for hematologists to exchange knowledge and learn about advances in the biology and treatment of bone marrow failure.
Desmond’s presentation, titled, ‘Overexpression of Integrin ?9 Cooperates with the Loss of Runx1 and Runx3 in Leukemogenesis’, was awarded the 3rd prize among oral presenters whose abstracts were chosen from more than 60 abstracts.
Congratulations to Desmond!
Overexpression of Integrin ?9 Cooperates with the Loss of Runx1 and Runx3 in Leukemogenesis
Desmond Wai Loon Chin1, Chelsia Qiuxia Wang1,2, Jing Yuan Chooi1, Giselle Sek Suan Nah1, Branko Cirovic1, Vinay Tergaonkar2, Ichiro Tanuichi3 and Motomi Osato1,4,5,6
1 National University of Singapore, Cancer Science Institute of Singapore, Singapore
2 A*STAR, Institute of Molecular and Cell Biology, Singapore
3 RIKEN Research Center for Allergy and Immunology, Yokohama, Japan
4 A*STAR, Institute of Bioengineering and Nanotechnology, Singapore
5 National University of Singapore, Department of Paediatrics, Singapore
6 Kumamoto University, International Research Center for Medical Sciences, Kumamoto, Japan
Background: Chromosomal translocations associated with RUNX family transcription factors, such as t(8;21) and inv(16), are frequently observed in human acute myeloid leukemia (AML). These chromosomal abnormalities produce fusion proteins which suppress function and/or expression of both RUNX1 and RUNX3. We previously reported that Runx1fl/fl;Runx3fl/fl;Mx1-Cre+ [double knockout (DKO)] mice exhibited two paradoxical lethal phenotypes: bone marrow failure and myeloproliferative disorder. These contradictory manifestations were shown to be caused by defect in DNA repair pathway. Accumulation of non-repaired DNA damage leads to massive cell death, while occasional acquisition of oncogenic mutations result in leukemia development. In this study, we aim to identify cooperative genetic hits which cooperate with Runx1 and Runx3 deficiency in leukemogenesis.
Methods: To identify such cooperative genetic alterations, retroviral insertional mutagenesis (RIM) was performed on Runx1;Runx3 DKO mice. DKO and their control mice were injected with Moloney murine leukemic virus (MoMuLV) and monitored for disease presentation. Bone marrow transplantation and colony forming assay were conducted to validate the cooperativity. To correlate findings in mice to human AML, publicly available gene expression datasets were also analyzed.
Results: Runx1;Runx3 DKO mice showed shorter disease latency in RIM as compared to the control mice. Although MoMuLV inoculation commonly induce T cell leukemia/lymphoma, majority of the Runx1;Runx3 DKO mice developed biphenotypic leukemia with myeloid features. Retrovirus integrations into integrin ?9 (Itga9) locus, which resulted in Itga9 overexpression, were exclusively found in Runx1;Runx3 DKO mice. We confirmed that overexpression of Itga9 in Runx1;Runx3 DKO cells increased the incidence of leukemia. In human AML, high expression of ITGA9 was found in AML cells with t(8;21) and inv(16) and associated with a poor prognosis.
Conclusions: We identified Itga9 as a cooperative hit with Runx1 and Runx3 deficiencies in leukemogenesis. This synergism was confirmed in human RUNX-related leukemias. Better understanding of the cooperating mechanism between abnormalities in ITGA9 and RUNX transcription factors will give further directions in developing therapies for human leukemias.