Division of Hematological Malignancy

Issay Kitabayashi, Kazutsune Yamagata, Takuo Katsumoto, Yutaka Shima, Yoko Ogawara, Emi Takamatsu, Yuuki Kagiyama, Mai Suzuki, Yukino Machida, Shuhei Fujita, Makoto Nakagawa, Yukiko Aikawa, Mika Shino, Rieko Furuya

Introduction

Acute myeloid leukemia (AML) is the most common leukemia in Japan and U.S. With current standard chemotherapy, approximately 70% of adults with AML can be expected to attain complete remission status following appropriate induction therapy. However, many of the AML patients have a relapse and only 25-30% of young adults and fewer than 10% of older patients survive longer than 5 years, suggesting the presence of AML stem cells that are resistant to chemotherapy. Thus, AML stem cell eradication is thought to be crucial for the cure of AML. Chromosome abnormalities, which results in the generation of specific fusion genes, are observed in ~50% of AML patients. AML associated with fusion genes involving MLL, MOZ, CALM or NUP98 have an extremely poor outcome. Normal cytogenetics portend average-risk AML. Recent genome analysis revealed that mutations in NPM, IDH1/IDH2/TET2, DNMT3a, and FLT3 genes are often simultaneously observed in patients with normal cytogenetics.

Our team and what we do

Our research purpose is to establish new therapeutic methods by identifying molecular targets that are essential for the maintenance of AML cells, especially AML stem cells.

Research activities

Rearrangements involving the NUP98 gene resulting in fusions to several partner genes occur in AML and myelodysplastic syndromes. This study demonstrates that the second phenylalanine-glycine (FG) repeat domain of the NUP98 moiety of the NUP98-HOXA9 fusion protein is important for its cell immortalization and leukemogenesis activities. We demonstrate that NUP98-HOXA9 interacts with MLL via this FG repeat domain and that, in the absence of MLL, NUP98-HOXA9-induced cell immortalization and leukemogenesis are severely inhibited. Molecular analyses indicate that MLL is important for the recruitment of NUP98-HOXA9 to the HOXA locus and for NUP98-HOXA9-induced HOXA gene expression. Our data indicate that MLL is crucial for NUP98-HOXA9 leukemia initiation.

Eradication of chemotherapy-resistant leukemia stem cells is expected to improve treatment outcomes in patients with AML. In a mouse model of AML expressing the MOZ-TIF2 fusion, we found that Ring1A and Ring1B, components of Polycomb repressive complex 1, play crucial roles in maintaining AML stem cells. The deletion of Ring1A and Ring1B (Ring1A/B) from MOZ-TIF2 AML cells abolished self-renewal capacity and induced the expression of numerous genes including Glis2. Overexpression of Glis2 caused MOZ-TIF2 AML cells to differentiate into mature cells, whereas Glis2 knockdown in Ring1A/B-deficient MOZ-TIF2 cells inhibited differentiation. Thus, Ring 1A/B regulates and maintains AML stem cells in part by repressing Glis2 expression, which promotes their differentiation. These findings provide new insights into the mechanism of AML stem cell homeostasis and reveal novel targets for cancer stem cell therapy.