About

Dr. Jatinder Lamba is currently the associate dean for research and graduate education in the UF College of Pharmacy and a professor in the Department of Pharmacotherapy and Translational Research. In 2022, she was appointed the Frank A. Duckworth Eminent Scholar Chair. She completed her post-doctoral training at St. Jude Children’s Research Hospital in Memphis, Tennessee, and has previously served as an Associate Professor at the University of Minnesota, where she was involved in the Department of Experimental and Clinical Pharmacology and directed the Pathway driven Pharmacogenomics; University of Minnesota Alliance (PUMA) Institute of Personalized Medicine. Her research focuses on the identification, characterization, and clinical validation of genomic and epigenomic markers that predict therapeutic outcomes in cancer patients. Her work spans from preclinical basic research using cell line models to translational and clinical phases involving multi-institute clinical trials. The long-term goal of her research is to integrate pharmacogenetic testing into clinical practice to enhance the safety and efficacy of drug therapy. Dr. Lamba’s pharmacogenomics research on anti-leukemic agents has been funded by NIH/NCI since 2008, with her current work focusing on the pharmacogenomics and epigenomics of cytarabine in pediatric AML patients. Her group is developing algorithms to incorporate genetic and epigenetic markers with other prognostic factors to advance precision medicine in oncology, aiming to tailor chemotherapy for maximum benefit. She has made significant contributions, including the first identification of genetic polymorphisms in the CD33 gene predictive of response to CD33 targeted agents in AML. Her research also explores metabolomics differences and biomarkers of prognostic significance in pediatric AML, as well as utilizing transcriptomics to build leukemic stem cell signatures and drug response signatures with prognostic and predictive value. Dr. Lamba has served as chair of the Pharmacogenomics SIG at AACP and is currently vice-chair of the Pharmacogenomics focus group with AAPS. She has reviewed grants for NIH and international agencies, published over 90 research articles, and serves on editorial boards of several scientific journals. She is dedicated to training future scientists, having mentored multiple Ph.D. students, post-doctoral fellows, PharmD students, hematology-oncology fellows, and undergraduate students, including those from minority and underrepresented groups.

Research topics

• Genetics
• Biology
• Medicine
• Internal medicine
• Cancer research
• Oncology
• Immunology
• Pharmacology
• Bioinformatics
• Cell biology
• Molecular biology
• Computational biology

Selected publications

• Abstract 4511: Dual targeting of IKKβ and NR4A1 for AML therapy.

  Cancer Research · 2026-04-03

  article

  Abstract Acute myeloid leukemia (AML) is a common aggressive blood cancer with a lethality rate among the highest of all leukemia subtypes. Cure rates of available therapeutic options are very low, underscoring an urgent need to develop more effective drugs. Here we identify IKKβ and NR4A1 as two closely related, clinically meaningful drivers of AML progression, and develop a proteolysis targeting chimera (PROTAC) drug that degrades both the proteins. IKKβ and the downstream NF-κB signaling are aberrantly activated in around 40% AML patients. However, IKKβ inhibitors exhibit serious side effects such as neutrophilia, limiting their therapeutic development. As opposed to the previously reported AML-suppressive role, we found that NR4A1 can also promote AML pathogenesis in different contexts. Moreover, IKKβ and NR4A1 were found to be highly expressed in AMLs associated with poor clinical outcomes, positively regulate each other’s expression, and synergize to maintain AML cell viability. We designed, synthesized, and validated an array of celastrol-based PROTACs as celastrol binds to both IKKβ and NR4A1, and identified one lead PROTAC, A9, that effectively kills several AML cell lines and primary human AML cells. Mechanistically, A9-induced AML cell killing was found to be dependent on CRBN E3 ligase-mediated dual degradation of IKKβ and NR4A1. In vivo, A9 attenuated AML disease progression in a clinically relevant KMT2A::MLLT3 mouse model and didn’t induce neutrophilia. Our results reveal a potentially novel strategy to treat intractable and aggressive AMLs in the clinic. Citation Format: Chandra Kumar Maharjan, Yi Liu, Yufeng Xiao, Bristy Podder, Tyler Montgomery, Lei Wang, Myung-Chul Kim, Zeng Jin, Seyedehalaleh Anvar, Alexandra Stevens, Ryan Kolb, Chen Zhao, Zhijian Qian, Jatinder K. Lamba, Guangrong Zheng, Weizhou Zhang. Dual targeting of IKKβ and NR4A1 for AML therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4511.

  PublisherDOI

• cellMCD Effectively Discovers Drug Resistance and Sensitivity Genes for Acute Myeloid Leukemia

  Genes · 2026-01-01

  articleOpen access

  BACKGROUND: Rapid advances in biotechnology provide researchers with the opportunity to integrate omics profiles (genomics, epigenomics, transcriptomics, proteomics, etc.) with multiple phenotypes or experimental conditions. In cancers such as acute myeloid leukemia (AML), where combination therapies are standard of care, identifying genetic drivers of drug resistance requires evaluating how genes are associated with multiple drug response phenotypes. Statistical analyses associating omics profiles with multiple phenotypes yield multiple significance values and rankings for each of many genes. There is a great need to consolidate these multiple rankings into a consensus ranking to prioritize specific genes for detailed follow-up wet-lab or clinical studies. METHODS/RESULTS: Here, we evaluate the well-known Fisher's method, the sum of squared z-statistics (SSz), and the recently published cellMCD method as tools for gene prioritization. In simulation studies, cellMCD showed very similar or highly superior performance to the widely used Fisher's and SSz methods. These advantages were also observed in an example application involving a CRISPR drug screen of an acute myeloid leukemia cell line. CONCLUSIONS: In summary, our results indicate that cellMCD should be more widely used for prioritizing discoveries from multiple omic association studies. These methods are available as an R package on github.

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• Abstract 6409: Epigenetic regulation of drug and disease related genes impact outcomes in pediatric AML

  Cancer Research · 2025-04-21

  articleSenior author

  Abstract DNA methylation is dysregulated in Acute Myeloid Leukemia (AML), which can have significant impact on regulation and expression levels of genes involved in Pharmacokinetic/Pharmacodynamics of AML chemotherapy as well as genes involved in AML pathogenesis. Thus, in this study we evaluated methylation levels of these genes for association with outcome, in pediatric AML patients. DNA methylation data available from GEO and GDC datasets and gene expression data available from TARGET for the discovery cohort of patient treated on Children’s Oncology Group clinical trials (n=924) were evaluated by Cox proportional hazard analysis for association with event-free survival (EFS) and overall survival (OS) and Minimal Residual Disease after induction I (MRD1). The results were validated in an independent cohort of patients treated on AML02 trial (n=159). We identified 23 CpGs in drug pathway genes, and 43 CpGs within AML relevant genes, that were associated with at least one endpoint at p< 2.17×10-5. These included, ABCA3, a drug efflux transporter, with higher methylation associated with poor OS (HR= 1.23, p <10−12), EFS (HR= 1.14, p <10−10), and greater MRD1 positivity (p <10−5). KIT hypermethylation was associated with unfavorable outcomes (OS, HR= 1.22, p <10−9; EFS, HR= 1.15, p <10−7). Among other genes DNMT3B hypermethylation was also predictive of detrimental survival (OS, HR= 1.143, p= 0.04). These results were replicated in the validation cohort. Our study shows significant age-adjusted correlations between DNA methylation of some CpGs sites and gene expression level. In conclusion, this focused approach demonstrated impact of variation in DNA methylation of key genes of relevance to AML drugs or pathogenesis on clinical outcome in AML opening up opportunities to predict outcome and strategically utilize hypomethylating agents to improve outcome. Citation Format: Naifah Alshameri, Francisco Marchi, Xueyuan Cao, Stanley Pounds, Jatinder Lamba. Epigenetic regulation of drug and disease related genes impact outcomes in pediatric AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6409.

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• Abstract 4358: Single nucleotide polymorphisms located in PK/PD pathway genes of standard AML chemotherapy regimen predicts outcome in pediatric AML

  Cancer Research · 2025-04-21

  articleSenior author

  Abstract Acute Myeloid Leukemia (AML) is an aggressive hematologic cancer with poor treatment outcomes in pediatric patients, particularly due to high relapse rates and drug resistance. Standard treatment involves cytarabine (Ara-C), daunorubicin, and etoposide (ADE) but resistance to these drugs remains a significant challenge. To better understand the genetic factors influencing drug resistance and treatment outcomes, we conducted a pharmacogenomic analysis of genetic variants in AML-related and drug-metabolizing genes within the context of (ADE) chemotherapy regimen. We extracted SNPs in genes involved in pharmacological pathways of ADE as well as genes representative of myeloid panel from an existing set of genome-wide Illumina 2.5 Omni microarray data obtained from genomic DNA of 400 patients treated on multi-site AML02 [NCT00136084, n=167] and AML08 [NCT00703820, n=233] clinical trials. SNPs within +/-10 kb region of the gene locus were evaluated for associations with multiple clinical endpoints such as minimal residual disease after induction 1 (MRD1), event-free survival (EFS), and overall survival (OS), adjusting for genetic ancestry. Our analysis results showed that at a p value of <0.01, 215 SNPs in 52 genes were predictive of at least one of the outcomes. SNPs in solute carrier (SLC) transporters, including SLC22A1, SLC28A1, and SLC28A3, were linked to increased MRD1 positivity, indicating poor prognosis. SLC28A1 and A3 have been implicated in uptake of nucleoside analogs such as Ara-C. In contrast, SNPs in SLCO1B1 were predictive of better EFS and OS, suggesting that variations in drug uptake influences treatment outcomes. Five SNPs within the cytidine deaminase (CDA), involved in inactivation of Ara-C were associated with poorer EFS and OS. These SNPs were linked to higher CDA mRNA expression in blood, as per the GTEx database, and showed regulatory potential in chromatin states. SNP rs1048977 has been associated with reduced CDA enzyme activity, further corroborating its role in poor treatment outcomes. Among the myeloid panel genes SNPs in the AML-related gene RUNX1, CSF3R and CDKN2A were associated with poor clinical outcomes. SNPs in CSF3R and CDKN2A genes were predictive of poor EFS and OS. RUNX1 is a critical factor for myeloid differentiation, CSF3R is involved in neutrophil biology and activates the JAK/STAT pathway, while CDKN2A functions as a tumor suppressor and regulates the cell cycle. Dual mutations in CSF3R and CEBPA have been linked to high relapse rates in pediatric AML. In conclusion, our comprehensive pharmacogenomic analysis of genes involved in drug metabolism and AML pathogenesis has identified key genetic variants that influence treatment outcomes. These findings, once validated in larger cohorts, could offer new opportunities for personalizing chemotherapy and improving prognosis prediction in pediatric AML patients. Citation Format: Aneesha Nath, Richard Marrero, Xueyuan Cao, Jeffrey E. Rubnitz, Stanley Pounds, Jatinder K. Lamba. Single nucleotide polymorphisms located in PK/PD pathway genes of standard AML chemotherapy regimen predicts outcome in pediatric AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4358.

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• A genome-wide association study using HapMap cell lines reveals modulators of cellular response to cyclophosphamide

  Future Oncology · 2025-05-13 · 1 citations

  articleOpen accessSenior authorCorresponding

  AIMS: This study identifies single-nucleotide polymorphisms (SNPs) associated with cellular response to cyclophosphamide (CTX) using phosphoramide mustard (PM), its primary cytotoxic metabolite, and explores the downstream consequences for breast cancer (BC) patients. METHODS: = 155) and without CTX. RESULTS: = 0.040). CONCLUSION: Our study identifies SNPs significantly associated with cellular CTX response with potential mechanistic and clinical relevance, thereby providing insights toward optimized CTX treatment strategies.

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• Donor and recipient genetic variants in drug metabolizing enzymes and transporters affect early tacrolimus pharmacokinetics after liver transplantation

  Scientific Reports · 2025-07-02 · 5 citations

  articleOpen access

  This study examines the influence of single nucleotide polymorphisms in drug metabolizing enzymes CYP3A4, CYP3A5, and UGT1A4, and the transporter ABCB1 on tacrolimus dose requirements and blood trough level variability in the period immediately after liver transplantation. We analyzed genotypes for these genes in 61 adult liver transplant recipients who received tacrolimus and their respective donors. Significant findings include increased average daily deviation (ADD) from the therapeutic range in patients with: donor CYP3A4*22 GG (1.68 [1.01, 2.29] versus 0.68 [0.42, 1.46] ng/mL/day, p = 0.016), recipient ABCB1 rs2032582 CT/TT (2.07 [1.68, 2.39] versus 1.37 [0.76, 1.95] ng/mL/day , p = 0.013), and donor UGT1A4*3 TT (1.69 [1.02, 2.42] versus 1.33 [0.54, 1.79] ng/mL/day , p = 0.043). Additionally, higher tacrolimus concentration/weight-adjusted dose ratios [C0/D ratio, (ng/mL)/(mg/kg/d)] were observed in recipients with CYP3A4*1B rs2740574 genotype TT (77.5 [60.7, 143.8] versus 47.5 [26.3, 64.0] (ng/mL)/(mg/kg/d), p = 0.0001), or CYP3A5*3 rs776746 genotype GG (74.9 [55.7, 147.4] versus 59.3 [36.1, 79.0] (ng/mL)/(mg/kg/d), p = 0.011), and in donor livers with CYP3A4*22 genotype GA/AA (131.5 [86.2, 187.1] versus 68.2 [47.1, 108.7] (ng/mL)/(mg/kg/d), p = 0.028). These findings demonstrate that genetic polymorphisms in both donor and recipient significantly affect tacrolimus dose requirements and the ability to maintain the target therapeutic tacrolimus levels in the immediate post-transplant period, emphasizing the role of precision medicine in optimizing immunosuppression therapeutic drug dosing.

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• A prospective, single site, single-arm pilot study of CPX-351 (Vyxeos) in individuals <22 years with secondary myeloid neoplasms

  Blood · 2025-11-03

  article

  Abstract Background and Significance: Secondary myeloid neoplasms (SMN) in children and adolescents are rare malignancies with dismal prognosis, lacking unified treatment approaches. SMN encompass therapy-related myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) and MDS/AML arising from bone marrow failure and germline predisposition syndromes. While hematopoietic stem cell transplantation (HSCT) remains the only curative option, outcomes remain poor with historical survival rates up to 45%. CPX-351 (Vyxeos®) is a liposomal formulation of cytarabine and daunorubicin in a fixed 5:1 molar ratio. CPX-351 demonstrated superior efficacy compared to standard chemotherapy in adult secondary AML, leading to FDA approval in 2017. The liposomal encapsulation preferentially accumulates in bone marrow and leukemic cells while potentially reducing systemic toxicity. There are no standardized treatment approaches for pediatric SMN and standard AML-type chemotherapy is associated with severe toxicity. Our institutional experience with CPX-351 in 7 pediatric patients with newly diagnosed SMN, all attaining complete morphologic remission with acceptable toxicity (Blood Adv 2022, PMID: 34710216), provided rationale for this study. Study Design and Methods: This single-center, single-arm pilot study (ClinicalTrials.gov: NCT05656248) evaluates CPX-351 safety, tolerability, and efficacy in patients <22 years with SMN at St. Jude Children's Research Hospital. The study population includes patients with treatment-related MDS/AML (previously treated with chemotherapy/radiation) and secondary MDS/AML arising from inherited bone marrow failure syndromes (e.g. severe congenital neutropenia, Shwachman-Diamond syndrome and others) or germline predisposition syndromes involving mutations in GATA2, RUNX1, ERCC6L2, NF1, ETV6, TP53, and others). Patients with higher-risk MDS (5-20% blasts) are reviewed at interdisciplinary conference to determine eligibility for HSCT; if a decision is made that cytoreductive therapy is warranted, patients are offered enrollment on the trial. Additional inclusion criteria include adequate renal, hepatic, and cardiac function, adequate performance status, and cumulative doxorubicin-equivalent dose <400/500mg/m² (without/with cardioprotection). Key exclusion criteria include de novo AML, JMML, constitutional trisomy 21, telomere biology disorders, Fanconi anemia, other DNA repair disorders, Wilson disease, and cumulative anthracycline exposure beyond standard safety limits. Treatment consists of CPX-351 100 units/m² (cytarabine 100mg/m² + daunorubicin 44mg/m²) on days 1, 3, and 5 of cycle 1. Cycle 2 administration depends on response: patients achieving complete remission (CR) with incomplete recovery (CRi) with measurable residual disease (MRD) <0.1% receive reduced-dose cycle of CPX-351 if HSCT is delayed (65mg/m² cytarabine + 29mg/m² daunorubicin), while patients with persistent disease receive standard dosing (if cumulative anthracycline exposure permits). If HSCT cannot be performed within 3-4 weeks after cycle 2, interim therapy options include additional FLT3 inhibitors for those patients with activating FLT3 mutations, or venetoclax alone or in combination. Response is assessed by bone marrow examination on Day 22 of each cycle with blast enumeration and MRD via flow cytometry (0.1% sensitivity). The primary endpoint is evaluated using Simon's two-stage minimax design (n=25), with 80% power to detect a composite CR/CRi rate ≥70%. Tolerability monitoring employs a three-stage design with 88.8% power to declare the therapy tolerable success (defined as completing 2 cycles without grade 4-5 non-hematologic toxicity) when the true tolerability success rate is 70%. Secondary endpoints include characterization of toxicity (including respiratory and cardiac), biological correlates of response, and 3-year overall and event-free survival of patients who received 1 or 2 courses of CPX-351 followed by HSCT. Exploratory objectives include analysis of pharmacogenomic response scores and bulk/single-cell genomic studies.The trial opened in January 2023, with 24 of 25 planned patients enrolled as of July 2025 (15 male). Ages at enrollment range from 4 to 19 years, with diverse racial representation (10 white, 3 multiracial, 2 black, 1 Asian, 1 Pacific Islander, 7 unreported). No stopping rules have been triggered, and recruitment has proceeded without major protocol modifications.

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• GWAS-guided pharmacogenomic risk scores predict premedication-related pegaspargase hypersensitivity and toxicities in pediatric and adolescent young adults with acute lymphoblastic leukemia or lymphoma

  Blood · 2025-11-03

  articleOpen accessSenior author

  Abstract Background: The addition of asparaginase to chemotherapy regimens has played a key role in significantly improving outcomes in pediatric and adolescent/young adult (AYA) patients with acute lymphoblastic leukemia (ALL), with >90% overall survival (OS). The use of pegaspargase (PEG), the PEGylated form of asparaginase commonly used in such regimens, is mainly limited by hypersensitivity reactions and associated toxicities. This frequently leads to switching to an alternate form of asparaginase isolated from Erwinia chrysanthemi (ERW). While response to ERW use after hypersensitivity is equivalent to PEG, limitations such as higher cost, greater dose requirement due to pharmacokinetic differences, pain when administered intramuscularly, and higher nausea make this substitution less convenient. A prospective multi-institutional study initiated by Rady Children's Health/Children's Hospital of Orange County (CHOC) evaluated the efficacy of pre-medicating pediatric and AYA patients with B or T-ALL or lymphoblastic lymphoma (Lly) with histamine-1 (H1) and histamine-2 (H2) blockers before PEG administration in preventing hypersensitivity reactions. Here, we describe a genome-wide association study (GWAS) leading to the development of pharmacogenomic risk scores for PEG-related hypersensitivity and Grade ≥ 3 toxicities in this cohort. Patients and Methods: GWAS was performed using genomic and clinical data from a cohort of 87 pediatric or AYA patients with ALL/Lly. Median age was 8.3 years, 65.5% were male, and 55.2% identified as Hispanic. Overall, 18 (20.7%) patients had a grade >2 PEG hypersensitivity reaction and 44 (50.6%) had an incidence of CTCAE, V5 grade ≥3 toxicities (hyperbilirubinemia, hyper/hypoglycemia, hypertriglyceridemia, pancreatitis, or thrombosis) within ≤30 days of PEG infusion. Infinium GSA-24 v3.0 was used to genotype 650k SNPs and post standard QC, 233,798 SNPs were tested for association with PEG hypersensitivity and toxicities by logistic regression analysis using PLINK. All SNPs significantly associated with each endpoint were used in multi-SNP predictor models testing all possible 2-SNP combinations across additive, dominant or recessive modes of inheritance. 1000 permutations/model were performed to determine likelihood of obtaining them falsely, and models with low Bayesian Information Criterion (BIC; <90) and a 1000 permutation p<0.05 were selected as significantly associated with the outcome. Genotype scores for unique SNPs within top models were assigned based on modes of inheritance and direction of their association (negative for favorable and positive for detrimental) and composite pharmacogenomic risk scores were calculated as the sum of genotype scores. Results: In our GWAS, 77 SNPs associated with the incidence of grade >2 PEG hypersensitivity (p < 0.002) and 81 SNPs associated with grade ≥3 toxicities (p < 0.001). Eight SNPs from 5 2-SNP combinations associated with hypersensitivity and were used to develop the composite PEG Hypersensitivity Risk Score. Similarly, 11 unique SNPs from six 2-SNP combinations for toxicity were used to develop a composite PEG Toxicity Risk Score. Both scores were stratified into low and high score groups based on the median. The distribution of these groups did not differ by sex, ethnicity (Hispanic or non-Hispanic), or NCI risk groups (standard or high). However, all patients with a hypersensitivity reaction were within high Hypersensitivity Risk Score group, while significantly higher incidences of grade >3 toxicities were observed in those within high Toxicity Risk Score group compared to those in low toxicity risk score group (toxicities incidence: 85% v 14% in high score or low score, respectively; p = <0.0001). Conclusion: Our results describe the GWAS-guided development of polygenic risk scores predicting PEG hypersensitivity and toxicity incidences. This approach eliminates certain biases associated with a candidate selection approach to build pharmacogenomic risk scores. Validation of these scores in a similar cohort as well as functional validations will be performed in the near future. In conclusion, we provide promising pharmacogenomic SNP models which could allow clinically relevant pre-medication or asparaginase format choice to minimize hypersensitivity and toxicities in pediatric or AYA patients with ALL/Lly.Funding for this study was provided by CHOC PSF Tithe Grant, CHOC Hyundai Cancer Institute Research Grant, and Servier Pharmaceuticals.

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• Proteomics reveals COX7B as a prognostically relevant oxphos-linked protein in pediatric AML

  Blood · 2025-11-03

  articleOpen accessSenior author

  Abstract Introduction: Acute myeloid leukemia (AML) is a complex and highly heterogeneous hematologic malignancy with poor clinical outcomes. Despite improvements in supportive care, the standard treatment for AML has remained largely unchanged since the 1970s through use of cytarabine in combination with anthracyclines. The approval of only a limited number of new antileukemic agents since 2017 highlights the urgent need for innovative approaches to identify factors contributing to relapse, drug resistance, and therapeutic failure. This study aims to elucidate the prognostic and therapeutic relevance of proteomics in AML. Methods: Global proteomic analysis of leukemic cells obtained at diagnosis from 97 pediatric patients treated in the St. Jude AML02 clinical trial was performed using Tandem Mass Tag (TMT) labeling followed by two-dimensional Liquid Chromatography (LC/LC) and Tandem Mass Spectroscopy (MS/MS). Data were preprocessed with median normalization and log transformation and batch correction. Proteomic signatures were compared across patient subgroups, clinical characteristics, and AML-linked genetic alterations and with survival outcomes as event free survival (EFS), overall survival (OS) and measurable residual disease after induction 1 (MRD1). Results: Among the most significantly expressed proteins (p < 0.001), 25 proteins were associated with poor clinical outcomes and 16 proteins were associated with superior outcomes. Among the proteins predictive of poor outcome significant enrichment was observed in metabolic pathways. COX7B (cytochrome C oxidase subunit 7B), a component of mitochondrial complex IV involved in the oxidative phosphorylation involved in oxidative phosphorylation (OXPHOS) pathway was strongly associated with adverse prognosis (EFS, HR=2.6; OS, HR=3.8, both p<0.001). Given that leukemic stem cells (LSCs) depend on OXPHOS for survival making it a potential therapeutic target. These findings are consistent with previous reports showing that elevated mRNA levels of mitochondrial/OXPHOS genes to be associated with poor outcome in AML. SLC25A15, a mitochondrial amino acid and proton transport, was also associated with poor prognosis (EFS, HR=3.5, OS, HR=5.3 both p<0.001 and MRD1, OR=4.2, p=0.03). SCL25A15 is frequently upregulated in cancers and contributes to cancer progression and poor prognosis. Among other metabolic pathway enzymes associated with poor prognosis included fumarate hydratase with role in TCA cycle, lysophospholipase (shown to modulate LSCs response), 3-ketodihydrosphingosine reductase, dehydrogenase/reductase 13, mitochondrialaspartyl-tRNA synthetase 2, protein O-glucosyltransferase 1, protein O-fucosyltransferase 1 and glucosidase. Other proteins associated with poor prognosis included ODR4, belonging to G protein coupled receptor signaling (p < 0.001, EFS and OS) and NLE, involved in Notch signaling pathway with a role in hematopoietic stem cell homoeostasis. Among proteins predictive of better clinical outcome included GRB10, a growth factor receptor bound protein 10, ALOX5AP, Creatinine kinase B, microtubule associated protein, deoxyribonucleae etc. Conclusions: This study represents one of the first and most comprehensive global proteome profiling of diagnostic bone marrow samples from pediatric AML patients. We report several metabolic enzymes that are predictive of poor outcome and specifically COX7B and its role in OXPHOS pathway is highly relevant as LSC survival is dependent on OXPHOS highlighting its therapeutic potential. Understanding the molecular mechanisms behind these distinct protein patterns may guide the development of precision therapies as well as identify novel drug targets in AML. Our ongoing study is in the process of expanding this analysis to a full cohort of 448 patient samples across multiple clinical trials.

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• Pharmacogenetic variants in UGT1A1/UGT1A3 and ABCC2 associate with deferasirox efficacy in transfusion-dependent thalassemia.

  Blood · 2025-11-03

  articleOpen accessSenior author

  Abstract Background: Patients with transfusion-dependent thalassemia (TDT) require blood transfusions generally every 2-5 weeks, depending on disease severity. The high iron burden that results from frequent blood transfusions can lead to organ dysfunction, therefore iron chelation is a critical part of therapy for all patients with TDT. Deferasirox (DFX) is a tridentate oral iron chelator indicated for patients ≥ 2 years old with TDT. However, ~30% of TDT patients do not respond to DFX, for reasons that are not understood. To evaluate if pharmacokinetic differences in patients might impact DFX efficacy and/or toxicity, a single center, prospective pharmacokinetic study was undertaken at UCSF Benioff Children's Hospital over 2 years. This study is focused on evaluating the impact of selected pharmacogenetic variants in key genes in DFX pharmacology. Patients and Methods: Blood samples were obtained for pharmacogenomic testing from patients (age ≥ 2 years) enrolled in this study during their regular clinic visits, prior to blood transfusion. Institutional Review Boards at the University of Florida and UCSF approved the study.DNAfrom these samples were genotyped for rs887829 and rs4124874 in UGT1A1 and rs2273697 in ABCC2 SNP using TaqMan-based genotyping assay (QuantStudio3). Association between SNP genotypes and DFX efficacy markers 1) serum ferritin levels (above or within target range of 500-1000 mg/mL) and 2) LIC (above or within target range of <7 mg/g) was tested using logistic regression analyses (RStudio v4.5.1). The Genotype-Tissue Expression (GTEx) portal was utilized to explore the relationship between respective SNP and gene expression in liver. Results: Overall, 49 patients were included, the median age of the participants was 34.5 years (range 2-63), with 47% identifying as female and 53% as male. SNP rs2273697 (G>A) in ABCC2/MRP2 (multidrug resistance-associated protein 2), which is involved in the excretion of DFX from hepatocytes into bile, was associated with increased serum ferritin levels above the target range (p <0.001). Gene expression data from GTEx database shows that the rs2273697 (G>A) change is associated with higher intron expression ratio of ABCC2/MRP2 in the liver. As part of the UDP-glucuronosyltransferase (UGT) family, UGT1A1 is involved primarily in DFX inactivation, while UGT1A3 plays a minor role. We tested 2 SNPs in UGT1A1/UGT1A3, rs4124874 (T>G) and rs887829 (C>T) for association with DFX efficacy in this cohort. For patients with the rs887829 T allele (TT and CT genotypes), 47% had LIC exceeding the target range compared to only 21% with CC genotype. Similarly, for rs4124874, 42% patients with GG and GT genotypes had LIC exceeding the target range compared to only 13% in those with TT genotype (both p <0.001). For rs887829 presence of T allele (CT and TT genotype) was also associated with high serum ferritin levels (p=0.002). Both the UGT SNPs were also significantly associated with higher hepatic gene expression levels of UGT1A1 and UGT1A3 in data from GTEx. These results imply decreased effectiveness of DFX and thus elevated LIC or serum ferritin levels above the target range. Conclusions: Overall, our data show that 3 SNPs in ABCC2/MRP2 and UGT1A1/UGT1A3 are significantly associated with reduced DFX efficacy in our study population. Despite a small patient cohort, our finding highlights that genetic testing has the potential to be incorporated in clinical management when initiating DFX monotherapy or concomitant therapy to optimize clinical outcomes. Our ongoing work is focused on expansion of the list of SNPs to include other key variants in DFX pharmacology and further investigate the association of candidate SNPs with DFX-induced toxicities (grade ≥3) such as renal failure, hepatic failure, and gastrointestinal hemorrhage based on selected toxicity markers. Overall, our goal is to improve therapy and quality of life for patients with TDT, and reduce toxicity-related mortality.

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Recent grants

• NIH Grant R21CA155524

  NIH · $439k · 2015

• Genomics of AML Prognosis

  NIH · $5.3M · 2008–2026

Frequent coauthors

• Stanley Pounds

  212 shared

• Xueyuan Cao

  University of Tennessee Health Science Center

  202 shared

• Jeffrey E. Rubnitz

  199 shared

• Raul C. Ribeiro

  St. Jude Children's Research Hospital

  182 shared

• Soheil Meshinchi

  175 shared

• Todd A. Alonzo

  Children's Oncology Group

  153 shared

• Susana C. Raimondi

  St. Jude Children's Research Hospital

  141 shared

• Alan S. Gamis

  Children's Mercy Hospital

  141 shared

Labs

• Department of Pharmacotherapy and Translational ResearchPI

Education

• Ph.D., Experimental and Clinical Pharmacology

  University of Minnesota

• Other

  St. Jude Children’s Research Hospital

Awards & honors

• Frank A. Duckworth Eminent Scholar Chair (2022)
• Pharmacogenomics SIG Chair at AACP (2013)
• Review grants for Italian Ministry of Health