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1. Clonal evolution and heterogeneity in AML

We played a key role in the development of a novel high-throughput single-cell DNA sequencing platform, Tapestri?, which enables high-throughput single-cell targeted DNA sequencing of primary patient samples. In the Genome Research paper, we described the technical principle of the platform and the feasibility of single cell genotyping in primary AML samples. We subsequently performed a large-scale single-cell genotyping study in 123 AML samples and described the clonal heterogeneity, evolution, and dynamics in AML at single-cell level (published in Nature Communications). In the same paper, we also described the proof of principle for DAb-seq (DNA-Antibody sequencing) that simultaneously evaluates genotype and immunophenotype of AML cells for the first time. In a paper recently published in Nature Communications, we also described the role of clonal heterogeneity and selection of resistant clones in the resistance mechanisms for IDH inhibitors in AML. These studies advanced our understanding of the extent of clonal heterogeneity and its role in treatment resistance and outcomes in AML patients.

a.  Pellegrino M, Sciambi A, Treusch S, Gokhale K, Jacob J, Chen TX, Oldham W, Durruthy-Durruthy R, Matthews J, Kantarjian H, Futreal PA, Jones KW, Takahashi K, Eastburn D. Genome Research. 2018 Sep;28(9):1345-1352. PMID: 30087104 

b.  Morita K, Wang F, Jahn K, Kuipers J, Yan Y, Mathews J, Little L, Gumbs C, Chen S, Zhang J, Song X, Thompson E, Patel K, Bueso-Ramos C, DiNardo CD, Song X, Jabbour E, Andreeff M, Cortes J, Konopleva M, Bhalla K, Garcia-Manero G, Kantarjian H, Beerenwinkel N, Navin N, Futreal PA, Takahashi K. Nature Commun. 2020 Oct 21;11(1):5327. PMID33087716 

c.  Wang F, Morita K, DiNardo CD, Furudate K, Tanaka T, Yan Yuanqing, Patel KP, MacBeth KJ, Wu B, Liu G, Frattini M, Matthews JA, Little LD, Gumbs C, Song X, Zhang J, Thompson EJ, Kadia TM, Garcia-Manero G, Jabbour E, Ravandi F, Bhalla KN, Konopleva M, Kantarjian HM, Futreal PA, Takahashi K. Nature Commun. 2021. May 10;12(1):2607. PMID33972549 

d.  Lachowiez CA, Loghavi S, Zeng Z, Tanaka T, Kim YJ, Uryu H, Turkalj S, Jakobsen NA, Luskin MR, Duose DY, Tidwell RSS, Short NJ, Borthakur G, Kadia TM, Masarova L, Tippett GD, Bose P, Jabbour EJ, Ravandi F, Daver NG, Garcia-Manero G, Kantarjian H, Garcia JS, Vyas P, Takahashi K, Konopleva M, DiNardo CD. Blood Cancer Discov. 2023 Jul 5;4(4):276-293. doi: 10.1158/2643-3230.BCD-22-0205.PMID: 37102976 

2. Pathogenesis of therapy-related myeloid neoplasms

In a paper published in Lancet Oncology, we showed that therapy-related myeloid neoplasms (t-MNs) arise through the positive selection of clonal hematopoiesis under cancer chemotherapy/radiation therapy. This finding led to the novel understanding of how t-MNs develop. We subsequently published in Cell Stem Cell about the molecular mechanism of how PPM1D mutated clonal hematopoiesis expands under the therapeutic pressure of certain chemotherapy. In addition, we recently published in Blood that lenalidomide therapy promotes clonal expansion of TP53-mutated clonal hematopoiesis. Finally, our recent paper was recently accepted in Nature Genetics, which describes the impact of cancer chemotherapy on the evolution of normal HSCs to CH and t-MNs. These findings contributed to the development of a new areas of research investigating the interplay between specific CH mutations and external stressors.

a.  Hsu JI, Dayaram T, Tovy A, De Braekeleer E, Jeong M, Wang F, Zhang J, Heffernan TP, Gera S, Kovacs JJ, Marszalek JR, Bristow C, Yan Y, Garcia-Manero G, Kantarjian H, Vassiliou G, Futreal PA, Donehower LA, Takahashi K*, Goodell MA*. (*co-corresponding authors) Cell Stem Cell 2018 Nov 1;23(5):700-713. PMID: 30388424 

b.  Sperling AS, Guerra VA, Kennedy JA, Yan Y, Hsu JI, Wang F, Nguyen AT, Miller PG, McConkey ME, Quevedo Barrios VA, Furudate K, Zhang L, Kanagal-Shamanna R, Zhang J, Little LD, Gumbs CE, Daver NG, DiNardo CD, Kadia TM, Ravandi F, Kantarjian HM, Garcia-Manero G, Futreal A, Ebert BL, Takahashi K. Blood. 2022 May 5, PMID:35512188 

c. Takahashi K, Wang F, Kantarjian H, Denaha D, Thompson E, Patel K, Neelapu S, Gumbs C, Wang Y, Bueso-Ramos C, DiNardo C, Colla S, Ravandi F, Zhang J, Wu X, Garcia-Manero G, Futreal PA. Lancet Oncology. 2017 Jan;18(1):100-111. PMID: 27923552 

d.  Uryu H, Saeki K, Haeno H, Kapadia CD, Furudate K, Nangalia J, Chapman MS, Zhao L,  Hsu JI, Zhao C, Chen S, Tanaka T, Li Z, Yang H, DiNardo C, Daver N, Pemmaraju N, Jain N, Ravandi F, Zhang J, Song X, Thompson E, Tang H, Little L, Gumbs C, Orlowski R, Qazilbash M, Bhalla K, Colla S, Kantarjian H, Shamanna RK, Bueso- Ramos C, Nakada D, Futreal PA, Shpall EJ, Goodell M, Garcia-Manero G, Takahashi K. Nature Genetics. Jul;57(7):1695-1707. PMID: 40596442.

3. Clonal hematopoiesis and its impact on oncologic care

We have been studying the biological and clinical implications of clonal hematopoiesis in cancer patients. In a paper published in Blood Cancer Discovery, we demonstrated that clonal hematopoiesis is associated with an increased risk of neurotoxicity after chimeric antigen receptor (CAR)-T cell therapy. In addition, we showed that clonal hematopoiesis is linked with an increased risk of graft-versus-host-disease (GvHD) in allogeneic stem cell transplant.

a.  Saini NY, Swoboda DM, Greenbaum U, Ma J, Patel RD, Devashish K, Das K, Tanner MR, Strati P, Nair R, Fayad L, Ahmed S, Lee HJ, Iyer SP, Steiner R, Jain N, Nastoupil L, Loghavi S, Tang G, Bassett RL, Jain P, Wang M, Westin JR, Green MR, Sallman DA, Padron E, Davila ML, Locke FL, Champlin RE, Garcia-Manero G, Shpall EJ, Kabriaei P, Flowers CR, Jain MD, Wang F, Futreal PA, Gillis N, Neelapu SS, Takahashi K. Blood Cancer Discov. 2022 May 9 PMID: 35533245 

b.  Oran B, Champlin RE, Wang F, Tanaka T, Saliba RM, Al-Atrash G, Garcia-Manero G, Kantarjian H, Cao K, Shpall EJ, Alousi AM, Mehta RS, Popat U, Futreal A, Takahashi K. Leukemia. 2022 Jan; 36(1):257-262. PMID: 34135465 

c.  Morita K, Kantarjian H, Wang F, Patel K, Bueso-Ramos C, Issa G, Song X, Zhang J, Tippen S, Thornton R, Coyle M, Little L, Gurtis G, Ravandi F, Kadia T, Daver N, DiNardo CD, Konopleva M, Andreeff M, Cortes J, Garcia-Manero G, Jabbour E, Futreal PA, Takahashi K. J Clin Oncol. 2018 Apr 27 PMID 29702001 

d.  Tanaka T, Morita K, Loghavi S, Wang F, Furudate K, Sasaki Y, Little L, Gumbs C, Matthews J, Daver N, Pemmaraju N, DiNardo CD, Sasaki K, Yilmaz M, Kadia TM, Ravandi F, Konopleva MY, Kantarjian HM, Champlin RE, Gl-Atrash G, Garcia-Manero G, Wang SA, Futreal PA, Takahashi K. Blood. 2021 Nov 4;138(18):1733-1739. PMID: 34115096  

4. Molecular subtypes hematologic malignancies

Through unbiased multi-omic genomic characterization, we have elucidated the novel molecular subtypes in various hematologic malignancies and its association with clinical phenotype. The paper in Nature Communications reported for the first time, molecular subtypes of adult MPAL (mixed phenotype acute leukemia) and association with clinical response to therapies. We also reported the landscape and prognostic significance of somatic mutations in CLL and myeloproliferative disorders. These studies led to the broader understandings of molecular heterogeneity in hematologic malignancies. 

a.   Takahashi K (corresponding author), Wang F, Morita K, Yan Y, Hu P, Zhao P, Abou Zahr A, Wu CJ, Gumbs C, Little L, Tippen S, Thornton R, Coyle M, Mendoza M, Thompson E, Zhang J, DiNardo CD, Jain N, Ravandi F, Cortes J, Garcia-Manero G, Takaori-Kondo A, Patel K, Konopleva M, Kantarjian H, Futreal PA. Nature Commun. 2018 Jul 10;9(1):2670, PMID: 29991687

b. Takahashi K, Hu B, Wang F, Yan Y, Kim E, Vitale C, Patel KP, Strati P, Gumbs C, Little L, Tippen S, Song X, Zhang J, Jain N, Thompson P, Garcia-Manero G, Kantarjian H, Estrov Z, Do KA, Keating M, Burger JA, Futreal PA, Wierda WG. Blood 2018 Jan 22. e-Pub. PMID: 2935183

c. J Takahashi K, Patel K, Kantarjian H, Luthra R, Pierce S, Cortes J, Verstovsek S. Blood. 2013 Nov 28;122(23):3784-6. PMID: 24068492

d.  Takahashi K, Pemmaraju N, Strati P, Nogueras-Gonzalez G, Ning J, Bueso-Ramos C, Luthra R, Pierce S, Cortes J, Kantarjian H, Garcia-Manero G. (2013). Blood. 2013 Oct 17;122(16):2807-11. PMID: 23896412 

5. Basic mechanisms in HSC biology and leukemogenesis

We are interested in understanding the basic biology of normal hematopoietic stem cells and the molecular mechanisms of leukemogenesis. These studies are done through close collaboration with other laboratories. 

a.   Tsai JJ, Dudakov JA, Takahashi K, Shieh JH, Velardi E, Holland AM, Singer NV, West ML, Smith OM, Young LF, Shono Y, Ghosh A, Hanash AM, Tran HT, Moore MA, van den Brink MR. Nature Cell Biol. 15(3):309-16, 3/2013. e-Pub 2/2013. PMCID: PMC3699879 

b.  Hu T, Morita K, Hill MC, Jiang Y, Kitano A, Saito Y, Wang F, Mao X, Hoegenauer KA, Morishita K, Martin JF, Futreal PA, Takahashi K, Nakada D. Blood. 134(8);614-625. PMID: 31270104

c.  Shi X, Jiang Y, Kitano A, Hu T, Murdaugh RL, Li Y, Hoegenauer KA, Chen R, Takahashi K, Nakada D. Sci Adv. 2021 Jul 21;7(30):eabf3895. PMID: 34290089 

d.  Ramabadran R, Wang JH, Reyes JM, Guzman AG, Gupta S, Rosas C, Brunetti L, Gundry MC, Tovy A, Long H, Gu T, Cullen SM, Tyagi S, Rux D, Kim JJ, Kornblau SM, Kyba M, Stossi F, Rau RE, Takahashi K, Westbrook TF, Goodell MA. Nature Cell Biol. 2023 Apr;25(4):528-539. PMID:37024683

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