Multistep leukemogenesis caused by imbalanced GATA1 function

2018 Fiscal Year Final Research Report

• Project/Area Number: 15H04759
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Tohoku University
• Principal Investigator: Shimizu Ritsuko 東北大学, 医学系研究科, 教授 (40226262)
• Co-Investigator(Kenkyū-buntansha): 平野 育生 東北大学, 医学系研究科, 助教 (00708117)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 白血病 / 転写因子

Outline of Final Research Achievements

Somatic GATA1 gene mutations leading to the production of GATA1s that lacks the amino-terminal transactivation domain is both requisite and sufficient for the development of the preleukemic condition referred to as transient myeloproliferative disorder (TMD) for acute megakaryoblastic leukemia (AMKL) in Down-syndrome newborns. We have established mice exclusively expressing GATA1s which phenocopy the human TMD. In this research, we found that reduced apoptosis and increased proliferation capacities in GATA1s megakaryocyte progenitors are involved in the pathogenesis of TMD. We also found that megakaryocyte progenitors with relatively lower level of GATA1s reduced in differentiation potency, consequently the progenitors persistently stay in mice and the mice are prone to develop leukemia. Higher amount of GATA1s expression partially compensates the defect in megakaryocyte maturation mediated through the Ras signaling cascade and enable progenitors to pass quickly without transformation.

Free Research Field

血液学

Academic Significance and Societal Importance of the Research Achievements

遺伝子変異の蓄積が白血病をはじめとするがんの発症機構に関わっていると考えられている。本研究では、GATA1転写因子の質的異常と量的異常の両方がそれぞれ異なった分子メカニズム（増殖・分化・細胞死調節）の破綻を引き起こし、それらの異常の複合として白血病発症に至ることを明らかにした。本解析により、多段階発がん機構においてさらなる理解が進むものと考えられる。