BACSI253U1#803U053U663U201U173U1#511U73U923U1#904U2#093UHT1#722U1#793U183U1#003U832U69U2#314U403U363U613U642U1#024U833U281U321U88U1#524U463U942U2#55U48U591U24U632U082U891U53U2#643U203U702U49U09U471U682U543U492U472U252U391U1#903U401U1#144U151U202U421UKAHKIn 2017, through single cell DNA sequencing and xenogeneic transplanta-1008060402055Targeting BIRC2/4Targeting BCL2Targeting MCL1Targeting AURKBTargeting KIF10AML > normal HSPCsOutcomeComplexChromosome 5Chromosome 7Chromosome 17t(3;3)11q23t(6;9)Chemical screeningtion, we identified mutated FLT3 as a critical molecule directly associated with in vivo leukemia initiation. Further, imbalance between anti-apoptotic and pro-apoptotic molecules at the inner mitochondrial membrane causes treat-ment resistance against FLT3 inhibition. Since the FLT3 mutation is detected in 20% of patients with acute myeloid leukemia (AML), we set out to identify therapeutic targets in the remaining 80% of AML patients. To this end, we integrated multiple methods such as DNA sequencing, RNA sequencing, and chemical screening using leukemia initiating cells derived from poor progno-sis patients. From bioinformatic analyses of transcriptome data, we found that several pathways such as anti-apoptosis, cell cycle, and immune regulation were enriched in AML initiating cells as compared with normal hematopoietic stem/progenitor cells (HSPCs). With chemical screening using 36 compounds, we further identified five compounds targeting BIRC2/4, BCL2, MCL1, AURKB, and KIF10 that could effectively eliminate patient AML cells. Using two com-pounds to which patient-derived AML cells showed the highest sensitivity, we confirmed that potent therapeutic efficacy could be achieved in a patient-de-rived xenograft model. Finally, we aimed to connect chromosomal aberrations and somatic mutations with drug sensitivity/resistance in individual patients. This study might provide potentially curative precision medicine for AML pa-tients who are not cured with current medical therapeutics.Figure: Identification of patient leukemia-specific vulnerabilities(A) Interaction among genes upregulated in AML compared with normal HSPCs is shown (left). Genes in the red circle are related with cellular survival. Interac-tion among the cell survival/cell death related genes is shown in the right panel. (B) In vitro chemical screening was setup using 36 compounds targeting molecules that were chosen from RNAseq results. (C) Viability of leukemic cells from 60 AML cases after treatment with five compounds identified in (B) is presented as a heat map. Purple columns in the outcome row indicate that the patients were deceased, gray (unknown) and pink (alive). Seven poor prognostic chromosomal aberrations are shown at the bottom.Recent Major PublicationsHashimoto M, Saito Y, Nakagawa R, Ogahara I, Takagi S, Takata S, Amitani H, Endo M, Yuki H, Manabe R, Watanabe T, Ozaki K, Kaneko A, Kajita H, Fujiki S, Sato K, Honma T, Uchida N, Okazaki Y, Ohara O, Shultz LD, Yamada M, Taniguchi S, Vyas P, de Hoon M, Momozawa Y, Ishikawa F. Maximal vulnerability converges to XIAP and BCL2 in leukemia with diverse genetic aberrations. Nature Cancer 2, 340-356, (2021)De Groot A, Saito Y, Kawakami E, Hashimoto M, Aoki Y, Ono R, Ogahara I, Fujiki S, Kaneko A, Watanabe T, Takagi M, Tomizawa D, Koh K, Eguchi M, Ishii E, Ohara O, Shultz LD, Mizutani S, Ishikawa F. Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukemia. EBioMedicine 64, 103235 (2021)Saito Y, Shultz L, Ishikawa F. Understanding normal and malignant human hematopoiesis using next-generation humanized mice. Trends Immunol 41, 706-720 (2020)Invited presentationsHashimoto M. “Integrative transcriptomic and chemical screening identifies patient-specific vulnerabilities in poor-prognosis AML” Japan Society of Hematology An-nual Meeting 2020 (Kyoto, Japan) October 2020Ishikawa F. “Identification of vulnerabilities in geneti-cally-complex AML” Australian Blood Club by Australian Society of Hematology (Online) October 2020.Ishikawa F. “Creating Treatment Strategies for Poor Prog-nosis Acute Myeloid Leukemia” Cancer Short Course at The Jackson Laboratory (Online) September 2020Ishikawa F. “Creating Treatment Strategies for Poor Prognosis Acute Myeloid Leukemia” Immuno-oncology workshop at National Cancer Institute (Online) July 2020100%80%60%40%20%0%Laboratory for Human Disease ModelsTeam Leader: Fumihiko Ishikawa
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