Selected Publications by Research Area

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.

1. High-throughput single-cell DNA sequencing of AML tumors with droplet microfluidics. 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 
2. Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics. 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 
3. Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia. 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 
4. A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies. 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

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.

1. PPM1D mutations driver clonal hematopoiesis in response to cytotoxic chemotherapy. 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 
2. Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms. 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 
3. Preleukaemic clonal hematopoiesis and the risk of therapy-related myeloid neoplasms: a case control study. 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 
4. Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation. 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.

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.

1. Clonal hematopoiesis is associated with increased risk of severe neurotoxicity in axicabtagene ciloleucel therapy of large B-cell lymphoma. 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 
2. Donor clonal hematopoiesis increases risk of acute graft versus host disease after matched sibling transplantation. 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 
3. Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia. 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 
4. Clonal dynamics and clinical implications of post-remission clonal hematopoiesis in acute myeloid leukemia. 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  

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. 

1. Integrative genomic analysis of adult mixed phenotype acute leukemia (MPAL) delineates lineage associated molecular subtypes. 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
2. Clinical implications of cancer gene mutations in patients with chronic lymphocytic leukemia treated with lenalidomide. 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
3. JAK2 p.V617F detection and allele burden measurement in peripheral blood and bone marrow aspirates in patients with myeloproliferative neoplasms. Takahashi K, Patel K, Kantarjian H, Luthra R, Pierce S, Cortes J, Verstovsek S. Blood. 2013 Nov 28;122(23):3784-6. PMID: 24068492
4. Clinical characteristics and outcomes of therapy-related chronic myelomonocytic leukemia. 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 

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. 

1. Nrf2 regulates haematopoietic stem cell function. 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 
2. PRDM16s transforms megakaryocyte-erythroid progenitors into myeloid leukemia–initiating cells. 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
3. Nuclear NAD+ homeostasis governed by NMNAT1 prevents apoptosis of acute myeloid leukemia stem cells. 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 
4. DNMT3A-coordinated splicing governs the stem state switch towards differentiation in embryonic and haematopoietic stem cells. 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