Professional Education

  • M.D., Harvard Medical School, Harvard-MIT Health Science and Technology (2020)

All Publications

  • Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms. Blood Sperling, A. S., Guerra, V. A., Kennedy, J. A., Yan, Y., Hsu, J. I., Wang, F., Nguyen, A. T., Miller, P. G., McConkey, M. E., Quevedo Barrios, V. A., Furudate, K., Zhang, L., Kanagal-Shamanna, R., Zhang, J., Little, L. D., Gumbs, C. E., Daver, N. G., DiNardo, C. D., Kadia, T. M., Ravandi, F., Kantarjian, H. M., Garcia-Manero, G., Futreal, A., Ebert, B. L., Takahashi, K. 2022


    There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies (CRT). Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiololgy of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Due to differences in CK1a degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.

    View details for DOI 10.1182/blood.2021014956

    View details for PubMedID 35512188

  • Mistaken Identity: Using Bone Scintigraphy to Diagnose Cardiac Amyloidosis in Patients With a Monoclonal Gammopathy JACC: CardioOncology Nguyen, A. T., Alexander, K. M. 2021; 3 (4): 594-597
  • Immune checkpoint inhibitor cardiotoxicity: Breaking barriers in the cardiovascular immune landscape. Journal of molecular and cellular cardiology Zhu, H., Ivanovic, M., Nguyen, A., Nguyen, P. K., Wu, S. M. 2021


    Immune checkpoint inhibitors (ICI) have changed the landscape of cancer therapy, but their use carries a high risk of cardiac immune related adverse events (iRAEs). With the expanding utilization of ICI therapy, there is a growing need to understand the underlying mechanisms behind their anti-tumor activity as well as their immune-mediated toxicities. In this review, we will focus on clinical characteristics and immune pathways of ICI cardiotoxicity, with an emphasis on single-cell technologies used to gain insights in this field. We will focus on three key areas of ICI-mediated immune pathways, including the anti-tumor immune response, the augmentation of the immune response by ICIs, and the pathologic "autoimmune" response in some individuals leading to immune-mediated toxicity, as well as local factors in the myocardial immune environment predisposing to autoimmunity. Discerning the underlying mechanisms of these immune pathways is necessary to inform the development of targeted therapies for ICI cardiotoxicities and reduce treatment related morbidity and mortality.

    View details for DOI 10.1016/j.yjmcc.2021.07.006

    View details for PubMedID 34303670

  • Pulmonary Artery Catheter Guided Therapy in Heart Failure Advances & Innovations in Heart Failure (AIHF): A Textbook of Cardiology Nguyen, A. T., Nohria, A. 2020
  • MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment NATURE Calvanese, V., Nguyen, A. T., Bolan, T. J., Vavilina, A., Su, T., Lee, L. K., Wang, Y., Lay, F. D., Magnusson, M., Crooks, G. M., Kurdistani, S. K., Mikkola, H. A. 2019; 576 (7786): 281-+


    Limited knowledge of the mechanisms that govern the self-renewal of human haematopoietic stem cells (HSCs), and why this fails in culture, have impeded the expansion of HSCs for transplantation1. Here we identify MLLT3 (also known as AF9) as a crucial regulator of HSCs that is highly enriched in human fetal, neonatal and adult HSCs, but downregulated in culture. Depletion of MLLT3 prevented the maintenance of transplantable human haematopoietic stem or progenitor cells (HSPCs) in culture, whereas stabilizing MLLT3 expression in culture enabled more than 12-fold expansion of transplantable HSCs that provided balanced multilineage reconstitution in primary and secondary mouse recipients. Similar to endogenous MLLT3, overexpressed MLLT3 localized to active promoters in HSPCs, sustained levels of H3K79me2 and protected the HSC transcriptional program in culture. MLLT3 thus acts as HSC maintenance factor that links histone reader and modifying activities to modulate HSC gene expression, and may provide a promising approach to expand HSCs for transplantation.

    View details for DOI 10.1038/s41586-019-1790-2

    View details for Web of Science ID 000502792400058

    View details for PubMedID 31776511

    View details for PubMedCentralID PMC7278275

  • Crbn(I391V) is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice BLOOD Fink, E. C., McConkey, M., Adams, D. N., Haldar, S. D., Kennedy, J. A., Guirguis, A. A., Udeshi, N. D., Mani, D. R., Chen, M., Liddicoat, B., Svinkina, T., Nguyen, A. T., Carr, S. A., Ebert, B. L. 2018; 132 (14): 1535–44


    Thalidomide and its derivatives, lenalidomide and pomalidomide, are clinically effective treatments for multiple myeloma and myelodysplastic syndrome with del(5q). These molecules lack activity in murine models, limiting investigation of their therapeutic activity or toxicity in vivo. Here, we report the development of a mouse model that is sensitive to thalidomide derivatives because of a single amino acid change in the direct target of thalidomide derivatives, cereblon (Crbn). In human cells, thalidomide and its analogs bind CRBN and recruit protein targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and subsequent degradation by the proteasome. We show that mice with a single I391V amino acid change in Crbn exhibit thalidomide-induced degradation of drug targets previously identified in human cells, including Ikaros (Ikzf1), Aiolos (Ikzf3), Zfp91, and casein kinase 1a1 (Ck1α), both in vitro and in vivo. We use the CrbnI391V model to demonstrate that the in vivo therapeutic activity of lenalidomide in del(5q) myelodysplastic syndrome can be explained by heterozygous expression of Ck1α in del(5q) cells. We found that lenalidomide acts on hematopoietic stem cells with heterozygous expression of Ck1α and inactivation of Trp53 causes lenalidomide resistance. We further demonstrate that CrbnI391V is sufficient to confer thalidomide-induced fetal loss in mice, capturing a major toxicity of this class of drugs. Further study of the CrbnI391V model will provide valuable insights into the in vivo efficacy and toxicity of this class of drugs.

    View details for DOI 10.1182/blood-2018-05-852798

    View details for Web of Science ID 000447005900014

    View details for PubMedID 30064974

    View details for PubMedCentralID PMC6172563

  • Medial HOXA genes demarcate haematopoietic stem cell fate during human development NATURE CELL BIOLOGY Dou, D. R., Calvanese, V., Sierra, M. I., Nguyen, A. T., Minasian, A., Saarikoski, P., Sasidharan, R., Ramirez, C. M., Zack, J. A., Crooks, G. M., Galic, Z., Mikkola, H. K. 2016; 18 (6): 595-?


    Pluripotent stem cells (PSCs) may provide a potential source of haematopoietic stem/progenitor cells (HSPCs) for transplantation; however, unknown molecular barriers prevent the self-renewal of PSC-HSPCs. Using two-step differentiation, human embryonic stem cells (hESCs) differentiated in vitro into multipotent haematopoietic cells that had the CD34(+)CD38(-/lo)CD90(+)CD45(+)GPI-80(+) fetal liver (FL) HSPC immunophenotype, but exhibited poor expansion potential and engraftment ability. Transcriptome analysis of immunophenotypic hESC-HSPCs revealed that, despite their molecular resemblance to FL-HSPCs, medial HOXA genes remained suppressed. Knockdown of HOXA7 disrupted FL-HSPC function and caused transcriptome dysregulation that resembled hESC-derived progenitors. Overexpression of medial HOXA genes prolonged FL-HSPC maintenance but was insufficient to confer self-renewal to hESC-HSPCs. Stimulation of retinoic acid signalling during endothelial-to-haematopoietic transition induced the HOXA cluster and other HSC/definitive haemogenic endothelium genes, and prolonged HSPC maintenance in culture. Thus, medial HOXA gene expression induced by retinoic acid signalling marks the establishment of the definitive HSPC fate and controls HSPC identity and function.

    View details for DOI 10.1038/ncb3354

    View details for Web of Science ID 000376750100006

    View details for PubMedID 27183470

    View details for PubMedCentralID PMC4981340