Tian Yi Zhang, MD, PhD

All Publications

• Effects of donor-engrafted clonal hematopoiesis in allogeneic and autologous stem cell transplantation: a systematic review and meta-analysis BONE MARROW TRANSPLANTATION Xie, Y., Kazakova, V., Weeks, L. D., Gerber, J. M., Tai, J., Zhang, T. Y., Lowsky, R., Wu, X., Yang, C., Patel, S. A. 2024

  Abstract

  Donor stem cell health may be critically important to the success of hematopoietic stem cell transplantation (HSCT). Herein, we performed this systematic review and meta-analysis including meta-regression to assess the impact of donor-engrafted clonal hematopoiesis (CH) in allogeneic HSCT (allo-HSCT) and impact of pre-transplant CH in autologous HSCT (auto-HSCT). We applied random-effects models to analyze 5 allo-HSCT studies with 3192 donor-recipient pairs and 9 auto-HSCT studies with 2854 patients. We found that donor-engrafted CH after allo-HSCT decreased the risk of disease relapse [Hazard Ratio (HR) = 0.79, 95% Confidence Interval (CI): (0.67, 0.93)], but did not affect overall survival (OS) [HR = 0.91, 95% CI: (0.75, 1.11)], progression-free survival (PFS) [HR = 0.94, 95% CI: (0.63, 1.41)], or non-relapse mortality [HR = 1.06, 95% CI: (0.81, 1.39)]. In contrast, pre-transplant CH in auto-HSCT recipients resulted in inferior OS [HR = 1.30, 95% CI: (1.16, 1.46)], inferior PFS [HR = 1.35, 95% CI: (1.18, 1.54)], and higher risk for therapy-related myeloid neoplasm [HR = 4.85, 95% CI: (2.39, 9.82)] when compared to auto-HSCT recipients without CH. This study sheds light onto the debate about prospective "CHIP screening" for stem cell donors and addresses the impact of CH as a transmissible phenomenon.

  View details for DOI 10.1038/s41409-024-02403-2

  View details for Web of Science ID 001297250400001

  View details for PubMedID 39183321

  View details for PubMedCentralID 4624443

• p53 immunohistochemistry as an ancillary tool for rapid assessment of residual disease in TP53-mutated acute myeloid leukemia and myelodysplastic syndromes. American journal of clinical pathology Brar, N., Lawrence, L., Fung, E., Zehnder, J. L., Greenberg, P. L., Mannis, G. N., Zhang, T. Y., Gratzinger, D., Oak, J., Silva, O., Kurzer, J., Tan, B., Menke, J. R., Fernandez-Pol, S. 2024

  Abstract

  Measurable residual disease flow cytometry (MRD-FC) and molecular studies are the most sensitive methods for detecting residual malignant populations after therapy for TP53-mutated acute myeloid leukemia and myelodysplastic neoplasms (TP53+ AML/MDS). However, their sensitivity is limited in suboptimal aspirates or when the immunophenotype of the neoplastic blasts overlaps with erythroids or normal maturing myeloid cells. In this study, we set out to determine if p53 immunohistochemistry (IHC) correlates with MRD-FC and next-generation sequencing (NGS) in the posttherapy setting and to determine the utility of p53 IHC to detect residual disease in the setting of negative or equivocal MRD-FC.We retrospectively identified 28 pre- and posttherapy bone marrow biopsy specimens from 9 patients with TP53+ AML/MDS and a p53 overexpressor phenotype by IHC (strong 3+ staining at initial diagnosis). Next-generation sequencing and/or MRD-FC results were collected for each specimen.Using a threshold of more than ten 2-3+ cells in any one 400× field, p53 IHC detected residual disease with a sensitivity of 94% and a specificity of 89%. The threshold used in this study showed a high degree of concordance among 6 blinded pathologists (Fleiss κ = 0.97).Our study suggests that p53 IHC can be used as a rapid tool (within 24 hours) to aid in the detection of residual disease that may complement MRD-FC or NGS in cases in which the flow cytometry immunophenotype is equivocal and/or the bone marrow aspirate is suboptimal.

  View details for DOI 10.1093/ajcp/aqae034

  View details for PubMedID 38643353

• Natural history of clonal haematopoiesis seen in real-world haematology settings. British journal of haematology Patel, S. A., Gerber, W. K., Zheng, R., Khanna, S., Hutchinson, L., Abel, G. A., Cerny, J., DaSilva, B. A., Zhang, T. Y., Ramanathan, M., Khedr, S., Selove, W., Woda, B., Miron, P. M., Higgins, A. W., Gerber, J. M. 2024

  Abstract

  Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real-world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non-sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real-world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non-sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high-risk CH in non-sole DTA (vs. sole DTA) patients and in progressors (vs. non-progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00-52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non-progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post-CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN.

  View details for DOI 10.1111/bjh.19423

  View details for PubMedID 38522849

• Analysis of Treatment Patterns and Outcomes in Patients Ages 60-74 in the PostVenetoclax Era St Martin, E. C., Schwede, M., Fakhri, B., Gotlib, J., Liedtke, M., Shomali, W., Zhang, T. Y., Mannis, G. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-190614

  View details for Web of Science ID 001159306705251

• Acute Myeloid Leukemia with Inv(3) or t(3;3): A Clinical and Cytogenetic Characterization of 40 Patients Moscvin, M., Schwede, M., Mannis, G., Zhang, T. Y. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-186672

  View details for Web of Science ID 001159740306277

• Sole DNMT3A/TET2/ASXL1 Mutations Define a Distinct Clinical Trajectory for Patients with Clonal Hematopoiesis Patel, S., Gerber, W. K., Zheng, R., Khanna, S., Hutchinson, L., Cerny, J., Dasilva, B., Zhang, T. Y., Khedr, S., Selove, W., Woda, B., Abel, G. A., Miron, P., Higgins, A., Gerber, J. M. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-182881

  View details for Web of Science ID 001159740306114

• Cladribine and Low-Dose Cytarabine-Based Salvage Therapy for Relapsed/Refractory AML in a Predominantly Venetoclax-Exposed Cohort Cheung, E., Schumann, C., Zhang, T. Y., Fakhri, B., Gotlib, J., Liedtke, M., Shomali, W., Mannis, G. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-185524

  View details for Web of Science ID 001159900803214

• The Shifting Prognosis of FLT3 Mutations in Acute Myeloid Leukemia in the Era of Targeted Therapy: A Real-World Study Using Large-Scale Electronic Health Record Data Schwede, M., Rodriguez, G., Henry, S., Wood, D., Mannis, G., Majeti, R., Chen, J., Bendavid, E., Zhang, T. Y. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-187725

  View details for Web of Science ID 001159306703227

• Harnessing Artificial Intelligence for Risk Stratification in Acute Myeloid Leukemia (AML): Evaluating the Utility of Longitudinal Electronic Health Record (EHR) Data Via Graph Neural Networks Sinha, R., Schwede, M., Ben Viggiano, Kuo, D., Henry, S., Wood, D., Mannis, G., Majeti, R., Chen, J., Zhang, T. Y. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-190151

  View details for Web of Science ID 001159306703229

• Development of Circulating Tumor DNA (ctDNA) for Molecular Measurable Residual Disease (MRD) in Acute Myeloid Leukemia (AML) Gunaratne, R., Zhou, C., Tai, J. W., Schwede, M., Tanaka, K., Alkaitis, M., Yin, R., Sworder, B. J., Mannis, G., Majeti, R., Khodadoust, M. S., Kurtz, D. M., Zhang, T. Y. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-181459

  View details for Web of Science ID 001159740307053

• Immunosuppression in Isocitrate Dehydrogenase Mutated Acute Myeloid Leukemia Tai, J. W., Li, G., Tanaka, K., Gopakumar, J., Zhou, C., Linde, M., Villar-Prados, A., Rangavajhula, A. S., Trotman-Grant, A. C., Landberg, N., Fan, A. C., Mannis, G., Zhang, T. Y. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-187981

  View details for Web of Science ID 001159306705096

• Phase 1b/2 Trial of Enasidenib in Lower-Risk MDS and Nonproliferative CMML without Isocitrate Dehydrogenase Type 2 Mutations Kuo, E., Santiago, V., Tanaka, K., Puram, V., Zhou, C., Tai, J. W., Mannis, G., Majeti, R., Zhang, T. Y. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-187644

  View details for Web of Science ID 001159306707106

• Phase IB OMNIVERSE Trial: Safety and Tolerability of Oral Azacitidine (Oral-AZA) in Combination With Venetoclax (VEN) for Treatment of Acute Myeloid Leukemia (AML) Fleming, S., Roboz, G. J., Fathi, A. T., Zhang, T. Y., Wei, A., Carraway, H. E., Holes, L., Petrlik, E., Prebet, T., Menezes, D. L., Bluemmert, I., Sun, H., Ravandi, F. CIG MEDIA GROUP, LP. 2023: S293

  View details for Web of Science ID 001062479600182

• Phase 1b OMNIVERSE trial: Safety and tolerability of oral azacitidine (Oral-AZA) in combination with venetoclax (VEN) for treatment of acute myeloid leukemia Fleming, S., Roboz, G. J., Fathi, A., Zhang, T., Wei, A., Carraway, H. E., Holes, L., Petrlik, E., Prebet, T., De Menezes, D., Bluemmert, I., Sun, H., Ravandi, F. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772004484

• Outcomes with molecularly targeted agents as salvage therapy following frontline venetoclax + hypomethylating agent in adults with acute myeloid leukemia: A multicenter retrospective analysis. Leukemia research Khanna, V., Azenkot, T., Liu, S. Q., Gilbert, J., Cheung, E., Lau, K., Pollyea, D. A., Traer, E., Jonas, B. A., Zhang, T. Y., Mannis, G. N. 2023; 131: 107331

  View details for DOI 10.1016/j.leukres.2023.107331

  View details for PubMedID 37263072

• The Goldilocks Dilemma in AML: Too Young and Fit, but Not Young and Fit Enough. Clinical lymphoma, myeloma & leukemia St Martin, E. C., Zhang, T. Y., Mannis, G. N. 2023

  View details for DOI 10.1016/j.clml.2023.03.011

  View details for PubMedID 37076365

• Reprogramming Cancer into Antigen Presenting Cells as a Novel Immunotherapy. Cancer discovery Linde, M. H., Fan, A. C., Kohnke, T., Trotman-Grant, A. C., Gurev, S. F., Phan, P., Zhao, F., Haddock, N. L., Nuno, K. A., Gars, E. J., Stafford, M., Marshall, P. L., Dove, C. G., Linde, I. L., Landberg, N., Miller, L. P., Majzner, R. G., Zhang, T. Y., Majeti, R. 2023

  Abstract

  Therapeutic cancer vaccination seeks to elicit activation of tumor-reactive T cells capable of recognizing tumor-associated antigens (TAAs) and eradicating malignant cells. Here, we present a cancer vaccination approach utilizing myeloid lineage reprogramming to directly convert cancer cells into tumor reprogrammed-antigen presenting cells (TR-APCs). Using syngeneic murine leukemia models, we demonstrate that TR-APCs acquire both myeloid phenotype and function, process and present endogenous TAAs, and potently stimulate TAA-specific CD4+ and CD8+ T cells. In vivo TR-APC induction elicits clonal expansion of cancer-specific T cells, establishes cancer-specific immune memory, and ultimately promotes leukemia eradication. We further show that both hematologic cancers and solid tumors, including sarcomas and carcinomas, are amenable to myeloid-lineage reprogramming into TR-APCs. Finally, we demonstrate the clinical applicability of this approach by generating TR-APCs from primary clinical specimens and stimulating autologous patient-derived T cells. Thus, TR-APCs represent a cancer vaccination therapeutic strategy with broad implications for clinical immuno-oncology.

  View details for DOI 10.1158/2159-8290.CD-21-0502

  View details for PubMedID 36856575

• Disease Characterization and Response Prediction in Myeloma Patients Undergoing Conventional and Cellular Therapies from Circulating Tumor DNA Hosoya, H., Carleton, M., Tanaka, K. L., Sworder, B., Hovanky, V., Duran, G. E., Zhang, T. Y., Khodadoust, M. S., Miklos, D. B., Arai, S., Iberri, D., Liedtke, M., Sidana, S., Kurtz, D. M. AMER SOC HEMATOLOGY. 2022: 1546-1548

  View details for DOI 10.1182/blood-2022-160370

  View details for Web of Science ID 000893223201226

• Outcomes with Molecularly Targeted Agents As Salvage Therapy Following Frontline HMA/Venetoclax in Adults with Acute Myeloid Leukemia: A Multi-Center Retrospective Analysis Khanna, V., Azenkot, T., Liu, S., Gilbert, J., Cheung, E., Lau, K., Pollyea, D. A., Traer, E., Jonas, B. A., Zhang, T. Y., Mannis, G. N. AMER SOC HEMATOLOGY. 2022: 3294-3296

  View details for DOI 10.1182/blood-2022-166803

  View details for Web of Science ID 000893223203147

• Feasibility Study Integrating Electronic Patient-Reported Outcomes (PROs) and Palliative Care for High-Risk Acute Myeloid Leukemia (AML) Patients Tan, I., Choi, J., Cunanan, K., Fronk, J., Zhang, T., Mannis, G. N., Ramchandran, K. CIG MEDIA GROUP, LP. 2021: S279-S280

  View details for Web of Science ID 000691910500447

• Niche-directed therapy in acute myeloid leukemia: optimization of stem cell competition for niche occupancy. Leukemia & lymphoma Patel, S. A., Dalela, D., Fan, A. C., Lloyd, M. R., Zhang, T. Y. 2021: 1-9

  Abstract

  Acute myeloid leukemia (AML) is an aggressive malignancy of stem cell origin that contributes to significant morbidity and mortality. The long-term prognosis remains dismal given the high likelihood for primary refractory or relapsed disease. An essential component of relapse is resurgence from the bone marrow. To date, the murine hematopoietic stem cell (HSC) niche has been clearly defined, but the human HSC niche is less well understood. The design of niche-based targeted therapies for AML must account for which cellular subsets compete for stem cell occupancy within respective bone marrow microenvironments. In this review, we highlight the principles of stem cell niche biology and discuss translational insights into the AML microenvironment as of 2021. Optimization of competition for niche occupancy is important for the elimination of measurable residual disease (MRD). Some of these novel therapeutics are in the pharmacologic pipeline for AML and may be especially useful in the setting of MRD.

  View details for DOI 10.1080/10428194.2021.1966779

  View details for PubMedID 34407733

• Reprogramming cancer into antigen presenting cells as a novel immunotherapy. Linde, M. H., Gurev, S. F., Phan, P., Zhao, F., Gars, E. J., Stafford, M., Kohnke, T., Marshall, P. L., Fan, A. C., Dove, C. G., Linde, I. L., Miller, L. P., Majzner, R. G., Zhang, T., Majeti, R. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000680263502148

• Routine use of gemtuzumab ozogamicin in 7 + 3-based inductions for all 'non-adverse' risk AML. Leukemia & lymphoma Ladha, A. n., Hui, G. n., Cheung, E. n., Berube, C. n., Coutre, S. E., Gotlib, J. n., Liedtke, M. n., Zhang, T. Y., Muffly, L. n., Mannis, G. N. 2021: 1–6

  View details for DOI 10.1080/10428194.2021.1876869

  View details for PubMedID 33491527

• Heterogeneous Definitions of Secondary Acute Myeloid Leukemia (AML) Yield Distinct Outcomes in Response to First-Line Treatment with Hypomethylating Agents (HMA) and Venetoclax (Ven) Tan, I., Schwede, M., Phan, P., Yin, R., Zhang, T. Y., Mannis, G. N. 2021

  View details for DOI 10.1182/blood-2021-147886

• Clinico-genomic profiling and clonal dynamic modeling of TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia. Leukemia & lymphoma Patel, S. A., Lloyd, M. R., Cerny, J., Shi, Q., Simin, K., Ediriwickrema, A., Hutchinson, L., Miron, P. M., Higgins, A. W., Ramanathan, M., Gerber, J. M. 2021: 1-13

  Abstract

  TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia have dismal outcomes. Here, we define the clinico-genomic landscape of TP53 disruptions in 40 patients and employ clonal dynamic modeling to map the mutational hierarchy against clinical outcomes. Most TP53 mutations (45.2%) localized to the L3 loop or LSH motif of the DNA-binding domain. TP53 disruptions had high co-occurrence with mutations in epigenetic regulators, spliceosome machinery, and cohesin complex and low co-occurrence with mutations in proliferative signaling genes. Ancestral and descendant TP53 mutations constituted measurable residual disease and fueled relapse. High mutant TP53 gene dosage predicted low durability of remission. The median overall survival (OS) was 280 days. Hypomethylating agent-based therapy served as an effective bridge to transplant, leading to improved median OS compared to patients who did not receive a transplant (14.7 vs. 5.1 months). OS was independent of the genomic location of TP53 disruption, which has implications for rational therapeutic design.

  View details for DOI 10.1080/10428194.2021.1957869

  View details for PubMedID 34496723

• Epstein-Barr virus-positive lymphoproliferative disorder manifesting as pulmonary disease in a patient with acute myeloid leukemia: a case report. Journal of medical case reports Dutta, R. n., Miao, S. Y., Phan, P. n., Fernandez-Pol, S. n., Shiraz, P. n., Ho, D. n., Mannis, G. N., Zhang, T. Y. 2021; 15 (1): 170

  Abstract

   Patients with lymphoproliferative disorders following hematopoietic stem cell transplant (HSCT) most commonly present with fever and lymphadenopathy within the first 5 months of transplant. Pulmonary post-transplant lymphoproliferative disorder (PTLD) is a particularly aggressive and rapidly progressive disease, with high morbidity and mortality. There are a very limited number of reported pulmonary PTLD cases following HSCT in patients with acute myeloid leukemia (AML). Early diagnosis and detection of pulmonary PTLD is critical given its high lethality. However, variable clinical presentations and nonspecific radiographic findings make pulmonary PTLD difficult to distinguish from other more common causes of pulmonary disease in AML patients.Here, we describe a 68-year-old Caucasian man who presented for salvage induction therapy following relapse of his AML after a haploidentical allogeneic HSCT 10 months earlier. He developed recurrent fevers, dry cough, and hypoxemia, with chest computed tomography (CT) showing bibasilar consolidations and increased nodularity without increased lymphadenopathy. His symptoms initially improved with antibiotic and antifungal therapy, but his follow-up chest CT showed progression of disease despite symptomatic improvement. Epstein-Barr virus (EBV) was detected in his blood by polymerase chain reaction (PCR), and a lung biopsy revealed monomorphic PTLD with B cells positive for EBV. Unfortunately, the patient's condition rapidly deteriorated, and he passed away prior to treatment initiation. To our knowledge, this is the first reported case of an AML patient developing pulmonary PTLD relatively late in his post-transplant course in the setting of relapsed disease and salvage therapy. Pulmonary PTLD, a rare but highly lethal disorder, can imitate the symptoms and radiographic findings of pneumonia, a common diagnosis in immunocompromised AML patients. This case illustrates the importance of considering pulmonary PTLD in the differential diagnosis for pulmonary disease in AML patients with a history of HSCT, especially in the setting of progressive radiographic findings despite broad antibacterial and antifungal therapy. Further, our case demonstrates the importance of biopsy and uninterrupted EBV DNA monitoring in the definitive diagnosis of PTLD, given nonspecific symptomatology and radiographic findings.

  View details for DOI 10.1186/s13256-021-02744-2

  View details for PubMedID 33773605

• Targeting LSCs: Peeling Back the Curtain on the Metabolic Complexities of AML. Cell stem cell Zhang, T. Y., Majeti, R. 2020; 27 (5): 693–95

  Abstract

  Most patients with AML succumb to chemoresistant leukemia stem cells (LSCs), which persist and reinitiate disease years after clinical remission. In this issue of Cell Stem Cell, Jones etal. (2020) identify a therapeutically targetable mechanism of resistance to venetoclax in relapsed and refractory AML LSCs mediated by nicotinamide metabolism.

  View details for DOI 10.1016/j.stem.2020.10.007

  View details for PubMedID 33157042

• Donor-derived acute promyelocytic leukemia presenting as myeloid sarcoma in a transplanted kidney. Leukemia Wong, R. L., Ketcham, M., Irwin, T., Akilesh, S., Zhang, T. Y., Reyes, J. D., Edlefsen, K., Jalikis, F., Becker, P. S. 2020

  View details for DOI 10.1038/s41375-020-0903-0

  View details for PubMedID 32523036

• IL-6 blockade reverses bone marrow failure induced by human acute myeloid leukemia. Science translational medicine Zhang, T. Y., Dutta, R., Benard, B., Zhao, F., Yin, R., Majeti, R. 2020; 12 (538)

  Abstract

  Most patients with acute myeloid leukemia (AML) die from complications arising from cytopenias resulting from bone marrow (BM) failure. The common presumption among physicians is that AML-induced BM failure is primarily due to overcrowding, yet BM failure is observed even with low burden of disease. Here, we use large clinical datasets to show the lack of correlation between BM blast burden and degree of cytopenias at the time of diagnosis. We develop a splenectomized xenograft model to demonstrate that transplantation of human primary AML into immunocompromised mice recapitulates the human disease course by induction of BM failure via depletion of mouse hematopoietic stem and progenitor populations. Using unbiased approaches, we show that AML-elaborated IL-6 acts to block erythroid differentiation at the proerythroblast stage and that blocking antibodies against human IL-6 can improve AML-induced anemia and prolong overall survival, suggesting a potential therapeutic approach.

  View details for DOI 10.1126/scitranslmed.aax5104

  View details for PubMedID 32269167

• Enasidenib drives human erythroid differentiation independently of isocitrate dehydrogenase 2. The Journal of clinical investigation Dutta, R. n., Zhang, T. Y., Köhnke, T. n., Thomas, D. n., Linde, M. n., Gars, E. n., Stafford, M. n., Kaur, S. n., Nakauchi, Y. n., Yin, R. n., Azizi, A. n., Narla, A. n., Majeti, R. n. 2020

  Abstract

  Cancer-related anemia is present in over 60% of newly diagnosed cancer patients and is associated with substantial morbidity and high medical costs. Drugs that enhance erythropoiesis are urgently required to decrease transfusion rates and improve quality of life. Clinical studies have observed an unexpected improvement in hemoglobin and red blood cell (RBC) transfusion-independence in AML patients treated with the isocitrate dehydrogenase 2 (IDH2) mutant-specific inhibitor, enasidenib, leading to improved quality of life without a reduction in AML disease burden. Here, we demonstrate that enasidenib enhanced human erythroid differentiation of hematopoietic progenitors. The phenomenon was not observed with other IDH1/2 inhibitors and occurred in IDH2-deficient CRIPSR-engineered progenitors independently of D-2-hydroxyglutarate. The effect of enasidenib on hematopoietic progenitors was mediated by protoporphyrin accumulation, driving heme production and erythroid differentiation in committed CD71+ progenitors rather than hematopoietic stem cells. Our results position enasidenib as a promising therapeutic agent for improvement of anemia and provide the basis for a clinical trial using enasidenib to decrease transfusion dependence in a wide array of clinical contexts.

  View details for DOI 10.1172/JCI133344

  View details for PubMedID 31895700

• Improved Outcomes of Octogenarians and Nonagenarians with Acute Myeloid Leukemia in the Era of Novel Therapies. American journal of hematology Jeng, M. Y., Dutta, R. n., Tan, I. T., Zhang, T. Y., Mannis, G. N. 2020

  View details for DOI 10.1002/ajh.25949

  View details for PubMedID 32744731

• Venetoclax and hypomethylating agent therapy in high risk myelodysplastic syndromes: a retrospective evaluation of a real-world experience. Leukemia & lymphoma Azizi, A. n., Ediriwickrema, A. n., Dutta, R. n., Patel, S. A., Shomali, W. n., Medeiros, B. n., Iberri, D. n., Gotlib, J. n., Mannis, G. n., Greenberg, P. n., Majeti, R. n., Zhang, T. n. 2020: 1–8

  Abstract

  Treatment with hypomethylating agents (HMAs) azacitidine or decitabine is the current standard of care for high risk myelodysplastic syndromes (MDSs) but is associated with low rates of response. The limited number of treatment options for patients with high risk MDS highlights a need for new therapeutic options. Venetoclax is an inhibitor of the BCL-2 protein which, when combined with an HMA, has shown high response rates in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of high risk MDS patients receiving combination HMA plus venetoclax in order to determine their effectiveness in this context. We show that in our cohort, the combination results in high response rates but is associated with a high frequency of myelosuppression. These data highlight the efficacy of combination HMA plus venetoclax in high risk MDS, warranting further prospective evaluation in clinical trials.

  View details for DOI 10.1080/10428194.2020.1775214

  View details for PubMedID 32543932

• Enasidenib Drives Maturation of Human Erythroid Precursors Independently of IDH2 Dutta, R., Zhang, T. Y., Koehnke, T., Thomas, D., Gars, E., Stafford, M., Nakauchi, Y., Kaur, S., Yin, R., Narla, A., Majeti, R. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-124551

  View details for Web of Science ID 000518218500371

• Human Acute Myeloid Leukemia Inhibits Normal Erythroid Differentiation through the Paracrine Effects of IL-6 Zhang, T. Y., Dutta, R., Zhao, F., Majeti, R. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-119297

  View details for Web of Science ID 000454837602287

• beta-Catenin is required for intrinsic but not extrinsic BCR-ABL1 kinase-independent resistance to tyrosine kinase inhibitors in chronic myeloid leukemia LEUKEMIA Eiring, A. M., Khorashad, J. S., Anderson, D. J., Yu, F., Redwine, H. M., Mason, C. C., Reynolds, K. R., Clair, P. M., Gantz, K. C., Zhang, T. Y., Pomicter, A. D., Kraft, I. L., Bowler, A. D., Johnson, K., Mac Partlin, M., O'Hare, T., Deininger, M. W. 2015; 29 (12): 2328–37

  Abstract

  Activation of nuclear β-catenin and expression of its transcriptional targets promotes chronic myeloid leukemia (CML) progression, tyrosine kinase inhibitor (TKI) resistance, and leukemic stem cell self-renewal. We report that nuclear β-catenin has a role in leukemia cell-intrinsic but not -extrinsic BCR-ABL1 kinase-independent TKI resistance. Upon imatinib inhibition of BCR-ABL1 kinase activity, β-catenin expression was maintained in intrinsically resistant cells grown in suspension culture and sensitive cells cultured in direct contact (DC) with bone marrow (BM) stromal cells. Thus, TKI resistance uncouples β-catenin expression from BCR-ABL1 kinase activity. In β-catenin reporter assays, intrinsically resistant cells showed increased transcriptional activity versus parental TKI-sensitive controls, and this was associated with restored expression of β-catenin target genes. In contrast, DC with BM stromal cells promoted TKI resistance, but had little effects on Lef/Tcf reporter activity and no consistent effects on cytoplasmic β-catenin levels, arguing against a role for β-catenin in extrinsic TKI resistance. N-cadherin or H-cadherin blocking antibodies abrogated DC-based resistance despite increasing Lef/Tcf reporter activity, suggesting that factors other than β-catenin contribute to extrinsic, BM-derived TKI resistance. Our data indicate that, while nuclear β-catenin enhances survival of intrinsically TKI-resistant CML progenitors, it is not required for extrinsic resistance mediated by the BM microenvironment.

  View details for DOI 10.1038/leu.2015.196

  View details for Web of Science ID 000366393900007

  View details for PubMedID 26202934

  View details for PubMedCentralID PMC4675686

• Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia LEUKEMIA Eiring, A. M., Page, B. G., Kraft, I. L., Mason, C. C., Vellore, N. A., Resetca, D., Zabriskie, M. S., Zhang, T. Y., Khorashad, J. S., Engar, A. J., Reynolds, K. R., Anderson, D. J., Senina, A., Pomicter, A., Arpin, C. C., Ahmad, S., Heaton, W. L., Tantravahi, S. K., Todic, A., Colaguori, R., Moriggl, R., Wilson, D. J., Baron, R., O'Hare, T., Gunning, P. T., Deininger, M. W. 2015; 29 (3): 586–97

  Abstract

  Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen-deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from chronic myeloid leukemia (CML) patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 μM) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells. Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation.

  View details for DOI 10.1038/leu.2014.245

  View details for Web of Science ID 000350734300008

  View details for PubMedID 25134459

  View details for PubMedCentralID PMC4334758

• KIT Signaling Governs Differential Sensitivity of Mature and Primitive CML Progenitors to Tyrosine Kinase Inhibitors CANCER RESEARCH Corbin, A. S., O'Hare, T., Gu, Z., Kraft, I. L., Eiring, A. M., Khorashad, J. S., Pomicter, A. D., Zhang, T. Y., Eide, C. A., Manley, P. W., Cortes, J. E., Druker, B. J., Deininger, M. W. 2013; 73 (18): 5775–86

  Abstract

  Imatinib and other BCR-ABL1 inhibitors are effective therapies for chronic myelogenous leukemia (CML), but these inhibitors target additional kinases including KIT, raising the question of whether off-target effects contribute to clinical efficacy. On the basis of its involvement in CML pathogenesis, we hypothesized that KIT may govern responses of CML cells to imatinib. To test this, we assessed the growth of primary CML progenitor cells under conditions of sole BCR-ABL1, sole KIT, and dual BCR-ABL1/KIT inhibition. Sole BCR-ABL1 inhibition suppressed mature CML progenitor cells, but these effects were largely abolished by stem cell factor (SCF) and maximal suppression required dual BCR-ABL1/KIT inhibition. In contrast, KIT inhibition did not add to the effects of BCR-ABL1 inhibition in primitive progenitors, represented by CD34(+)38(-) cells. Long-term culture-initiating cell assays on murine stroma revealed profound depletion of primitive CML cells by sole BCR-ABL1 inhibition despite the presence of SCF, suggesting that primitive CML cells are unable to use SCF as a survival factor upon BCR-ABL1 inhibition. In CD34(+)38(+) cells, SCF strongly induced pAKT(S473) in a phosphoinositide 3-kinase (PI3K)-dependent manner, which was further enhanced by inhibition of BCR-ABL1 and associated with increased colony survival. In contrast, pAKT(S473) levels remained low in CD34(+)38(-) cells cultured under the same conditions. Consistent with reduced response to SCF, KIT surface expression was significantly lower on CD34(+)38(-) compared with CD34(+)38(+) CML cells, suggesting a possible mechanism for the differential effects of SCF on mature and primitive CML progenitor cells.

  View details for DOI 10.1158/0008-5472.CAN-13-1318

  View details for Web of Science ID 000324806300017

  View details for PubMedID 23887971

  View details for PubMedCentralID PMC3894913

• Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice JOURNAL OF CLINICAL INVESTIGATION De Domenico, I., Zhang, T. Y., Koening, C. L., Branch, R. W., London, N., Lo, E., Daynes, R. A., Kushner, J. P., Li, D., Ward, D. M., Kaplan, J. 2010; 120 (7): 2395–2405

  Abstract

  Hepcidin is a peptide hormone that regulates iron homeostasis and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the transcription factor Stat3, resulting in a transcriptional response. Hepcidin treatment of ferroportin-expressing mouse macrophages showed changes in mRNA expression levels of a wide variety of genes. The changes in transcript levels for half of these genes were a direct effect of hepcidin, as shown by cycloheximide insensitivity, and dependent on the presence of Stat3. Hepcidin-mediated transcriptional changes modulated LPS-induced transcription in both cultured macrophages and in vivo mouse models, as demonstrated by suppression of IL-6 and TNF-alpha transcript and secreted protein. Hepcidin-mediated transcription in mice also suppressed toxicity and morbidity due to single doses of LPS, poly(I:C), and turpentine, which is used to model chronic inflammatory disease. Most notably, we demonstrated that hepcidin pretreatment protected mice from a lethal dose of LPS and that hepcidin-knockout mice could be rescued from LPS toxicity by injection of hepcidin. The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses.

  View details for DOI 10.1172/JCI42011

  View details for Web of Science ID 000279544000018

  View details for PubMedID 20530874

  View details for PubMedCentralID PMC2898601

• Macrophages from 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice exhibit an increased sensitivity to lipopolysaccharide stimulation due to TGF-beta-Mediated up-regulation of SHIP1 expression JOURNAL OF IMMUNOLOGY Zhang, T. Y., Daynes, R. A. 2007; 179 (9): 6325–35

  Abstract

  11beta-Hydroxysteroid dehydrogenase type 1 (11betaHSD1) performs end-organ metabolism of glucocorticoids (GCs) by catalyzing the conversion of C(11)-keto-GCs to C(11)-hydroxy-GCs, thereby generating activating ligands for the GC receptor. In this study, we report that 11betaHSD1(-/-) mice are more susceptible to endotoxemia, evidenced by increased weight loss and serum TNF-alpha, IL-6, and IL-12p40 levels following LPS challenge in vivo. Peritoneal and splenic macrophage (splnMphi) from these genetically altered mice overproduce inflammatory cytokines following LPS stimulation in vitro. Inflammatory cytokine overexpression by 11betaHSD1(-/-) splnMphi results from an increased activation of NF-kappaB- and MAPK-signaling cascades and an attenuated PI3K-dependent Akt activation. The expression of SHIP1 is augmented in 11betaHSD1(-/-) Mphi and contributes to inflammatory cytokine production because overexpression of SHIP1 in primary bone marrow Mphi (BMMphi) leads to a similar type of hyperresponsiveness to subsequent LPS stimulation. 11betaHSD1(+/+) and 11betaHSD1(-/-) BMMphi responded to LPS similarly. However, 11betaHSD1(-/-) BMMphi derived in the presence of elevated GC levels up-regulated SHIP1 expression and increased their capacity to produce inflammatory cytokines following their activation with LPS. These observations suggest the hyperresponsiveness of 11betaHSD1(-/-) splnMphi results from myeloid cell differentiation in the presence of moderately elevated GC levels found within 11betaHSD1(-/-) mice. GC-conditioning of BMMphi enhanced SHIP1 expression via up-regulation of bioactive TGF-beta. Consistently, TGF-beta protein expression was increased in unstimulated CD11b(-) cells residing in the BM and spleen of 11betaHSD1(-/-) mice. Our results suggest that modest elevations in plasma GC levels can modify the LPS responsiveness of Mphi by augmenting SHIP1 expression through a TGF-beta-dependent mechanism.

  View details for DOI 10.4049/jimmunol.179.9.6325

  View details for Web of Science ID 000250388000081

  View details for PubMedID 17947710

• Glucocorticoid conditioning of myeloid progenitors enhances TLR4 signaling via negative regulation of the phosphatidylinositol 3-kinase-Akt pathway JOURNAL OF IMMUNOLOGY Zhang, T. Y., Daynes, R. A. 2007; 178 (4): 2517–26

  Abstract

  The immunomodulatory effects of glucocorticoids (GCs) have been described as bimodal, with high levels of GCs exerting immunosuppressive effects and low doses of GCs being immunopermissive. While the mechanisms used by GCs to achieve immunosuppression have been investigated intensely, the molecular mechanisms underlying the permissive effects of GCs remain uncharacterized. Herein, we demonstrate that GC conditioning during the differentiation of myeloid progenitors into macrophages (Mphis) results in their enhanced LPS responsiveness, demonstrated by an overexpression of the inflammatory cytokines TNF-alpha, IL-6, and IL-12. Inflammatory cytokine overexpression resulted from an increased activation of NF-kappaB and the MAPK signaling cascade and a reduced activation of the PI3K-Akt pathway following LPS stimulation. GC conditioning during Mphi differentiation induced an increase in the expression of SHIP1, a phosphatase that negatively regulates the PI3K signaling pathway. Small interfering RNA-mediated knockdown of SHIP1 expression increased PI3K-dependent Akt activation and subsequently decreased inflammatory cytokine expression, suggesting GC-mediated up-regulation of SHIP1 expression is responsible for the augmentation in inflammatory cytokine production following LPS stimulation. We also show that splenic Mphis purified from normal mice that were implanted with timed-release GC pellets exhibited an enhanced LPS responsiveness and increased SHIP1 expression, indicating that GCs can regulate SHIP1 expression in vivo. Our results suggest that minor fluctuations in physiological levels of endogenous GCs can program endotoxin-responsive hemopoietic cells during their differentiation by regulating their sensitivity to stimulation.

  View details for DOI 10.4049/jimmunol.178.4.2517

  View details for Web of Science ID 000244026800062

  View details for PubMedID 17277160

• The expression of 11 beta-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities JOURNAL OF IMMUNOLOGY Zhang, T. Y., Ding, X. H., Daynes, R. A. 2005; 174 (2): 879–89

  Abstract

  The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes control the interconversion of active glucocorticoids (GCS) and their inactive 11-keto metabolites, a process commonly referred to as the cortisone/cortisol shuttle. Although the prereceptor metabolism of GCS by 11beta-HSD is well documented in a variety of cells and tissues, it has not yet been carefully investigated in the major cell types of the immune system. In this study, we demonstrate that 11beta-HSD1 transcripts, protein, and enzyme activities are actively expressed in murine CD4(+), CD8(+), and B220(+) lymphocytes, as well as CD11c(+) dendritic cells. Only reductase activity was observed in living cells, evidenced by the restricted conversion of cortisone to cortisol. Activation of CD4(+) T cells increased their 11beta-HSD1 activity, as did their polarization into Th1 or Th2 cells. CD4(+) T cells isolated from aged donors (>16 mo) had increased 11beta-HSD1 protein and an elevated capacity to convert cortisone to cortisol. The GCS generated in murine CD4(+) T cells from their inactive 11-keto metabolites could activate the GCS receptor, demonstrated by an up-regulation of IL-7Ralpha and GCS-induced leucine zipper gene expression. The presence of a functional 11beta-HSD1 provides lymphocytes with a novel intracrine regulatory mechanism that could influence such processes as lymphocyte development, effector function, and susceptibility to apoptosis. Thus, the presence of 11beta-HSD1 provides an additional means to facilitate GCS influences over lymphocyte activities, uncoupled from the plasma concentration of GCS.

  View details for DOI 10.4049/jimmunol.174.2.879

  View details for Web of Science ID 000226360500038

  View details for PubMedID 15634910

• Peroxisome proliferator-activated receptor alpha negatively regulates T-bet transcription through suppression of p38 mitogen-activated protein kinase activation JOURNAL OF IMMUNOLOGY Jones, D. C., Ding, X. H., Zhang, T. Y., Daynes, R. A. 2003; 171 (1): 196–203

  Abstract

  Expression of the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha) in resting lymphocytes was recently established, although the physiologic role(s) played by this nuclear hormone receptor in these cell types remains unresolved. In this study, we used CD4(+) T cells isolated from PPARalpha(-/-) and wild-type mice, as well as cell lines that constitutively express PPARalpha, in experiments designed to evaluate the role of this hormone receptor in the regulation of T cell function. We report that activated CD4(+) T cells lacking PPARalpha produce increased levels of IFN-gamma, but significantly lower levels of IL-2 when compared with activated wild-type CD4(+) T cells. Furthermore, we demonstrate that PPARalpha regulates the expression of these cytokines by CD4(+) T cells in part, through its ability to negatively regulate the transcription of T-bet. The induction of T-bet expression in CD4(+) T cells was determined to be positively influenced by p38 mitogen-activated protein (MAP) kinase activation, and the presence of unliganded PPARalpha effectively suppressed the phosphorylation of p38 MAP kinase. The activation of PPARalpha with highly specific ligands relaxed its capacity to suppress p38 MAP kinase phosphorylation and promoted T-bet expression. These results demonstrate a novel DNA-binding independent and agonist-controlled regulatory influence by the nuclear hormone receptor PPARalpha.

  View details for DOI 10.4049/jimmunol.171.1.196

  View details for Web of Science ID 000183674400025

  View details for PubMedID 12816998