Advances in the application of patient-derived xenograft models in acute leukemia resistance

Abstract

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are genetically heterogeneous malignancies of hematopoietic stem cells, characterized by complex mutations and a high risk of drug resistance and relapse. Patient-derived xenograft (PDX) models are dynamic entities transplanted with leukemia stem cells (LSCs), retaining patients’ biological and genetic characteristics. By elucidating LSCs, clonal dynamics, and microenvironment interaction, PDXs facilitate the preclinical evaluation of therapy sensitivity, including immunotherapies, epigenetic therapies, and other agents targeting mutated proteins or apoptosis. The application of PDXs has provided translational evidence for various studies with reliable clinical relevance. Additionally, conventional PDXs remain a robust tool in identifying drug resistance compared with other models, and their potential is further unleashed when examined in large cohorts or combined with novel technologies, which not only enhances our understanding of acute leukemia biology but also enables the discovery and identification of novel biomarkers. In this review, we present the application of PDX models for acute leukemia resistance, including mechanism investigation, therapy evaluation, and associated challenges.

Keywords

Patient-derived xenografts / acute leukemia / leukemia stem cells

References

[1] DiNardo CD,Freeman SD.Acute myeloid leukaemia.Lancet2023;401:2073-86

[2] Papaemmanuil E,Bullinger L.Genomic classification and prognosis in acute myeloid leukemia.N Engl J Med2016;374:2209-21 PMCID:PMC4979995

[3] Kurtz KJ,O’Keefe M,Rau RE.Murine models of acute myeloid leukemia.Front Oncol2022;12:854973 PMCID:PMC9214208

[4] Dozzo A,Shin JW,O’Driscoll CM.Modelling acute myeloid leukemia (AML): what’s new? A transition from the classical to the modern.Drug Deliv Transl Res2023;13:2110-41 PMCID:PMC10315355

[5] Döhner H,Löwenberg B.Towards precision medicine for AML.Nat Rev Clin Oncol2021;18:577-90

[6] Aparicio S,Kung AL.Examining the utility of patient-derived xenograft mouse models.Nat Rev Cancer2015;15:311-6

[7] Heckl D,Yudovich D.Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing.Nat Biotechnol2014;32:941-6 PMCID:PMC4160386

[8] Kaur M,Hu G.Induction and therapeutic targeting of human NPM1c⁺ myeloid leukemia in the presence of autologous immune system in mice.J Immunol2019;202:1885-94 PMCID:PMC6401260

[9] Rongvaux A,Martinek J.Development and function of human innate immune cells in a humanized mouse model.Nat Biotechnol2014;32:364-72 PMCID:PMC4017589

[10] Lapidot T,Vormoor J.A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.Nature1994;367:645-8

[11] Bulaeva E,Nakamichi N.MYC-induced human acute myeloid leukemia requires a continuing IL-3/GM-CSF costimulus.Blood2020;136:2764-73

[12] Díaz de la Guardia R,Gutiérrez-Agüera F.Engraftment characterization of risk-stratified AML in NSGS mice.Blood Adv2021;5:4842-54 PMCID:PMC9153030

[13] Notta F,Wang JC.Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells.Nature2011;469:362-7

[14] Sarry JE,Perry R.Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice.J Clin Invest2011;121:384-95 PMCID:PMC3007135

[15] Shlush LI, Zandi S, Mitchell A, et al; HALT Pan-Leukemia Gene Panel Consortium. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506:328-33. PMCID:PMC4991939

[16] Ishikawa F,Saito Y.Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region.Nat Biotechnol2007;25:1315-21

[17] González-García S,Fuentes P.IL-7R is essential for leukemia-initiating cell activity of T-cell acute lymphoblastic leukemia.Blood2019;134:2171-82 PMCID:PMC6933515

[18] Saito Y,Ogahara I.Overcoming mutational complexity in acute myeloid leukemia by inhibition of critical pathways.Sci Transl Med2017;9:eaao1214 PMCID:PMC6377281

[19] Reinisch A,Corces MR.A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells.Nat Med2016;22:812-21 PMCID:PMC5549556

[20] Paczulla AM,Konantz M.Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice.Haematologica2017;102:854-64 PMCID:PMC5477604

[21] Her Z,Paramasivam K.An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia.J Hematol Oncol2017;10:162 PMCID:PMC5639594

[22] Rehe K,Bomken S.Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations.EMBO Mol Med2013;5:38-51 PMCID:PMC3569652

[23] Kong Y,Saito Y.CD34+CD38+CD19+ as well as CD34+CD38-CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL.Leukemia2008;22:1207-13

[24] García-Peydró M,Mosquera M.The NOTCH1/CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model.J Clin Invest2018;128:2802-18 PMCID:PMC6025994

[25] Larrue C,Mouchel PL.Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells.Nat Commun2021;12:422 PMCID:PMC7813857

[26] Pei S,Gillen AE.A novel type of monocytic leukemia stem cell revealed by the clinical use of venetoclax-based therapy.Cancer Discov2023;13:2032-49 PMCID:PMC10527971

[27] Ferrando AA.Clonal evolution in leukemia.Nat Med2017;23:1135-45

[28] Kawashima N,Kim JH.Comparison of clonal architecture between primary and immunodeficient mouse-engrafted acute myeloid leukemia cells.Nat Commun2022;13:1624 PMCID:PMC8956585

[29] Morita K,Jahn K.Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics.Nat Commun2020;11:5327 PMCID:PMC7577981

[30] Wang K,Wang X.Patient-derived xenotransplants can recapitulate the genetic driver landscape of acute leukemias.Leukemia2017;31:151-8 PMCID:PMC5203983

[31] Klco JM,Miller CA.Functional heterogeneity of genetically defined subclones in acute myeloid leukemia.Cancer Cell2014;25:379-92 PMCID:PMC3983786

[32] Sandén C,Orsmark Pietras C.Clonal competition within complex evolutionary hierarchies shapes AML over time.Nat Commun2020;11:579 PMCID:PMC7002407

[33] Belderbos ME,Ausema B.Clonal selection and asymmetric distribution of human leukemia in murine xenografts revealed by cellular barcoding.Blood2017;129:3210-20

[34] Ebinger S,Ziegenhain C.Characterization of rare, dormant, and therapy-resistant cells in acute lymphoblastic leukemia.Cancer Cell2016;30:849-62 PMCID:PMC5156313

[35] Caserta C,Barcella M.miR-126 identifies a quiescent and chemo-resistant human B-ALL cell subset that correlates with minimal residual disease.Leukemia2023;37:1994-2005

[36] Ding L,Larson DE.Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing.Nature2012;481:506-10 PMCID:PMC3267864

[37] Shlush LI,Heisler L.Tracing the origins of relapse in acute myeloid leukaemia to stem cells.Nature2017;547:104-8

[38] Tzoneva G,Oshima K.Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia.Nature2018;553:511-4 PMCID:PMC5931372

[39] Elder A,Wilson I.Abundant and equipotent founder cells establish and maintain acute lymphoblastic leukaemia.Leukemia2017;31:2577-86 PMCID:PMC5558874

[40] Anderson K,van Delft FW.Genetic variegation of clonal architecture and propagating cells in leukaemia.Nature2011;469:356-61

[41] Richter A,Sekora A.The molecular subtype of adult acute lymphoblastic leukemia samples determines the engraftment site and proliferation kinetics in patient-derived xenograft models.Cells2022;11:150 PMCID:PMC8750004

[42] Drenberg CD,Pounds SB.Transcriptome profiling of patient derived xenograft models established from pediatric acute myeloid leukemia patients confirm maintenance of FLT3-ITD mutation.Leuk Lymphoma2017;58:247-50 PMCID:PMC5102776

[43] Ben-David U,Tseng YY.Patient-derived xenografts undergo mouse-specific tumor evolution.Nat Genet2017;49:1567-75 PMCID:PMC5659952

[44] Molina O,Thampi N.Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression.EMBO Mol Med2024;16:64-92 PMCID:PMC10897411

[45] Richter-Pechańska P,Bornhauser B.PDX models recapitulate the genetic and epigenetic landscape of pediatric T-cell leukemia.EMBO Mol Med2018;10:e9443 PMCID:PMC6284381

[46] Uzozie AC,Rolf N.PDX models reflect the proteome landscape of pediatric acute lymphoblastic leukemia but divert in select pathways.J Exp Clin Cancer Res2021;40:96 PMCID:PMC7958471

[47] Galán-Díez M,Kousteni S.The bone marrow microenvironment in health and myeloid malignancy.Cold Spring Harb Perspect Med2018;8:a031328 PMCID:PMC6027930

[48] Schepers K,Passegué E.Normal and leukemic stem cell niches: insights and therapeutic opportunities.Cell Stem Cell2015;16:254-67 PMCID:PMC4391962

[49] Witkowski MT,Aifantis I.Mapping and targeting of the leukemic microenvironment.J Exp Med2020;217:e20190589 PMCID:PMC7041707

[50] Wei J,Fox C.Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia.Cancer Cell2008;13:483-95 PMCID:PMC2486365

[51] Ellegast JM,Kovtonyuk LV.inv(16) and NPM1^mut AMLs engraft human cytokine knock-in mice.Blood2016;128:2130-4 PMCID:PMC5084606

[52] Piya S,Bhattacharya S.BETP degradation simultaneously targets acute myelogenous leukemia stem cells and the microenvironment.J Clin Invest2019;129:1878-94 PMCID:PMC6486356

[53] Habringer S,Herhaus P.Dual targeting of acute leukemia and supporting niche by CXCR4-directed theranostics.Theranostics2018;8:369-83 PMCID:PMC5743554

[54] Welschinger R,Basnett J.Plerixafor (AMD3100) induces prolonged mobilization of acute lymphoblastic leukemia cells and increases the proportion of cycling cells in the blood in mice.Exp Hematol2013;41:293-302.e1

[55] Cappelli LV,Phillip JM.Endothelial cell-leukemia interactions remodel drug responses, uncovering T-ALL vulnerabilities.Blood2023;141:503-18 PMCID:PMC10082359

[56] Shafat MS,Mohr S.Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment.Blood2017;129:1320-32

[57] Jia X,Yao Y,Chen K.Dynamic evolution of bone marrow adipocyte in B cell acute lymphoblastic leukemia: insights from diagnosis to post-chemotherapy.Cancer Biol Ther2024;25:2323765 PMCID:PMC10936623

[58] Duan CW,Chen J.Leukemia propagating cells rebuild an evolving niche in response to therapy.Cancer Cell2014;25:778-93

[59] Moschoi R,Nebout M.Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy.Blood2016;128:253-64

[60] Zhang W,Zhang H.Concomitant targeting of FLT3 and BTK overcomes FLT3 inhibitor resistance in acute myeloid leukemia through the inhibition of autophagy.Haematologica2023;108:1500-14 PMCID:PMC10230429

[61] Lehner KM,Kolb EA.Bone marrow microenvironment-induced chemoprotection in KMT2A rearranged pediatric AML is overcome by azacitidine-panobinostat combination.Cancers2023;15:3112 PMCID:PMC10296268

[62] Passaro D,Abarrategi A.Increased vascular permeability in the bone marrow microenvironment contributes to disease progression and drug response in acute myeloid leukemia.Cancer Cell2017;32:324-41.e6 PMCID:PMC5598545

[63] Zhang B,Zhao D.Treatment-induced arteriolar revascularization and miR-126 enhancement in bone marrow niche protect leukemic stem cells in AML.J Hematol Oncol2021;14:122 PMCID:PMC8351342

[64] Galán-Díez M,Ali AM.Subversion of serotonin receptor signaling in osteoblasts by kynurenine drives acute myeloid leukemia.Cancer Discov2022;12:1106-27 PMCID:PMC8983599

[65] Huan J,Goloviznina NA.Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes.Leukemia2015;29:2285-95 PMCID:PMC4834971

[66] Johnson SM,Parker C,Bradley H.Acute lymphoblastic leukaemia cells produce large extracellular vesicles containing organelles and an active cytoskeleton.J Extracell Vesicles2017;6:1294339 PMCID:PMC5373679

[67] Georgievski A,Thomas C.Acute lymphoblastic leukemia-derived extracellular vesicles affect quiescence of hematopoietic stem and progenitor cells.Cell Death Dis2022;13:337 PMCID:PMC9005650

[68] Dal Bello R,Joudinaud R.A multiparametric niche-like drug screening platform in acute myeloid leukemia.Blood Cancer J2022;12:95 PMCID:PMC9232632

[69] Borella G,Porcù E.Acute myeloid leukemia (AML) in a 3D bone marrow niche showed high performance for in vitro and in vivo drug screenings.Blood2019;134:544

[70] Selvaraju K,Gubat J.Sensitivity of acute myelocytic leukemia cells to the dienone compound VLX1570 is associated with inhibition of the ubiquitin-proteasome system.Biomolecules2021;11:1339 PMCID:PMC8470745

[71] Fazio M,Chuan Y,Zon LI.Zebrafish patient avatars in cancer biology and precision cancer therapy.Nat Rev Cancer2020;20:263-73 PMCID:PMC8011456

[72] Izumchenko E,Ciznadija D.Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors.Ann Oncol2017;28:2595-605 PMCID:PMC5834154

[73] Byrne AT,Amant F.Interrogating open issues in cancer precision medicine with patient-derived xenografts.Nat Rev Cancer2017;17:254-68

[74] Higuchi T,Hayashi K.High clinical concordance of drug resistance in patient-derived orthotopic xenograft (PDOX) mouse models: first step to validated precise individualized cancer chemotherapy.Anticancer Res2023;43:4277-84

[75] Li J,Zhao S,Bi L.Patient-derived intrafemoral orthotopic xenografts of peripheral blood or bone marrow from acute myeloid and acute lymphoblastic leukemia patients: clinical characterization, methodology, and validation.Clin Exp Med2023;23:1293-306 PMCID:PMC10390355

[76] Albert DH,Davies AM.Co-clinical modeling of the activity of the BET inhibitor mivebresib (ABBV-075) in AML.In Vivo2022;36:1615-27 PMCID:PMC9301399

[77] Stevens AM,Rashid R.Addressing a pre-clinical pipeline gap: development of the pediatric acute myeloid leukemia patient-derived xenograft program at Texas Children’s Hospital at Baylor College of Medicine.Biomedicines2024;12:394 PMCID:PMC10886789

[78] Ma J,Luo Y.Few-shot learning creates predictive models of drug response that translate from high-throughput screens to individual patients.Nat Cancer2021;2:233-44 PMCID:PMC8248912

[79] Gao H,Ferretti S.High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response.Nat Med2015;21:1318-25

[80] Townsend EC,Christodoulou A.The public repository of xenografts enables discovery and randomized phase II-like trials in mice.Cancer Cell2016;29:574-86 PMCID:PMC5177991

[81] Tanaka K,Dobashi Y.The first Japanese biobank of patient-derived pediatric acute lymphoblastic leukemia xenograft models.Cancer Sci2022;113:3814-25 PMCID:PMC9633318

[82] Lin S,Scheidegger NK.An in vivo CRISPR screening platform for prioritizing therapeutic targets in AML.Cancer Discov2022;12:432-49 PMCID:PMC8831447

[83] Bahrami E,Jurinovic V.Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo.Mol Cancer2023;22:107 PMCID:PMC10329331

[84] Wirth AK,Vosberg S.In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance.Leukemia2022;36:2863-74 PMCID:PMC9712105

[85] Carlet M,Vergalli J.In vivo inducible reverse genetics in patients’ tumors to identify individual therapeutic targets.Nat Commun2021;12:5655 PMCID:PMC8476619

[86] Gambacorta V,Ciccimarra M.Integrated multiomic profiling identifies the epigenetic regulator PRC2 as a therapeutic target to counteract leukemia immune escape and relapse.Cancer Discov2022;12:1449-61 PMCID:PMC9394393

[87] Vassiliou GS,Rad R.Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice.Nat Genet2011;43:470-5 PMCID:PMC3084174

[88] Ng ES,Li JY.Long-term engrafting multilineage hematopoietic cells differentiated from human induced pluripotent stem cells.Nat Biotechnol2024;

[89] Wu M,Liu S.Enhanced engraftment of human haematopoietic stem cells via mechanical remodelling mediated by the corticotropin-releasing hormone.Nat Biomed Eng2025;9:754-71

[90] Rudzinska-Radecka M,Mukherjee D,Piwocka K.High-throughput formulation of reproducible 3D cancer microenvironments for drug testing in myeloid leukemia.Biofabrication2024;17:015035

[91] Liu Y,Cai C,Shen H.Patient-derived xenograft models in cancer therapy: technologies and applications.Signal Transduct Target Ther2023;8:160 PMCID:PMC10097874

[92] Liu ACH,Yang Y.Targeting STAT5 signaling overcomes resistance to IDH inhibitors in acute myeloid leukemia through suppression of stemness.Cancer Res2022;82:4325-39

[93] Hegde S,Wunderlich M.Inhibition of the RacGEF VAV3 by the small molecule IODVA1 impedes RAC signaling and overcomes resistance to tyrosine kinase inhibition in acute lymphoblastic leukemia.Leukemia2022;36:637-47 PMCID:PMC8885421

[94] Wang Z,Li Y.Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China.Acta Pharm Sin B2021;11:1526-40 PMCID:PMC8245910

[95] Zhang Y,Wang Y.Sitravatinib as a potent FLT3 inhibitor can overcome gilteritinib resistance in acute myeloid leukemia.Biomark Res2023;11:8 PMCID:PMC9872318

[96] Janssen M,Bruch PM.Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1.Blood2022;140:2594-610

[97] Li D,Shang Z.Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD⁺ acute myeloid leukemia.Signal Transduct Target Ther2020;5:21 PMCID:PMC7067872

[98] Long J,Fang WY.FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia.Blood2020;135:1472-83

[99] Bisaillon R,Thiollier C.Genetic characterization of ABT-199 sensitivity in human AML.Leukemia2020;34:63-74

[100] Farge T,de Toni F.Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism.Cancer Discov2017;7:716-35 PMCID:PMC5501738

[101] Ding YY,Madden K.Targeting senescent stemlike subpopulations in Philadelphia chromosome-like acute lymphoblastic leukemia.Blood2025;145:1195-210 PMCID:PMC11923434

[102] Yadav BD,Wells JE.Heterogeneity in mechanisms of emergent resistance in pediatric T-cell acute lymphoblastic leukemia.Oncotarget2016;7:58728-42 PMCID:PMC5312271

[103] Beck D,Tian F.PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia.Nat Commun2024;15:9697 PMCID:PMC11549222

[104] Lopez-Millan B,Vinyoles M.NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLLr B-ALL by regulating NR3C1 expression.Blood2024;144:2002-17

[105] Meyer LK,Delgado-Martin C.Glucocorticoids paradoxically facilitate steroid resistance in T cell acute lymphoblastic leukemias and thymocytes.J Clin Invest2020;130:863-76 PMCID:PMC6994137

[106] Tremblay CS,Boyle JA.STAT5 activation promotes progression and chemotherapy resistance in early T-cell precursor acute lymphoblastic leukemia.Blood2023;142:274-89

[107] de Groot AP,Kawakami E.Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukaemia.EBioMedicine2021;64:103235 PMCID:PMC7878180

[108] Shi Y,Blair HJ.Phase II-like murine trial identifies synergy between dexamethasone and dasatinib in T-cell acute lymphoblastic leukemia.Haematologica2021;106:1056-66 PMCID:PMC8018112

[109] Laukkanen S,Yan C.Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia.Blood2022;140:1891-906 PMCID:PMC10082361

[110] Pallavi R,Durfort T.Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion.Nat Commun2024;15:828 PMCID:PMC10821871

[111] Hashimoto M,Nakagawa R.Combined inhibition of XIAP and BCL2 drives maximal therapeutic efficacy in genetically diverse aggressive acute myeloid leukemia.Nat Cancer2021;2:340-56

[112] Carlet M,Vergalli J.X-linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL.EMBO Mol Med2023;15:e14557 PMCID:PMC9832863

[113] Carter BZ,Tao W.Targeting MCL-1 dysregulates cell metabolism and leukemia-stroma interactions and resensitizes acute myeloid leukemia to BCL-2 inhibition.Haematologica2022;107:58-76 PMCID:PMC8719086

[114] Ramsey HE,Lee T.A novel MCL1 inhibitor combined with venetoclax rescues venetoclax-resistant acute myelogenous leukemia.Cancer Discov2018;8:1566-81 PMCID:PMC6279595

[115] Bhatt S,Olesinski EA.Reduced mitochondrial apoptotic priming drives resistance to BH3 mimetics in acute myeloid leukemia.Cancer Cell2020;38:872-90.e6 PMCID:PMC7988687

[116] Lewis AC,Tea MN.Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.Blood2022;139:3737-51 PMCID:PMC9642852

[117] Wu D,Hong Y.Integrated stress response activation induced by usnic acid alleviates BCL-2 inhibitor ABT-199 resistance in acute myeloid leukemia.J Adv Res2024;In Press:

[118] van der Zwet JCG,Cordo’ V.MAPK-ERK is a central pathway in T-cell acute lymphoblastic leukemia that drives steroid resistance.Leukemia2021;35:3394-405

[119] Tahir SK,Carneiro BA.Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia.Blood2023;141:2114-26 PMCID:PMC10646782

[120] Buettner R,Morales C.Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine.J Hematol Oncol2021;14:70 PMCID:PMC8074444

[121] Peris I,Martínez-Balsalobre E.Activation of the PP2A-B56α heterocomplex synergizes with venetoclax therapies in AML through BCL2 and MCL1 modulation.Blood2023;141:1047-59 PMCID:PMC10023731

[122] Xie C,Qin D.Bcl-2 inhibition combined with PPARα activation synergistically targets leukemic stem cell-like cells in acute myeloid leukemia.Cell Death Dis2023;14:573 PMCID:PMC10465498

[123] Lin KH,Xie A.Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer.Nat Genet2020;52:408-17 PMCID:PMC7398704

[124] Cheng Y,Pickering BF.N⁶-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.Cancer Cell2021;39:958-72.e8 PMCID:PMC8282764

[125] Qin X,Dong L.CRISPR screening reveals ZNF217 as a vulnerability in high-risk B-cell acute lymphoblastic leukemia.Theranostics2025;15:3234-56 PMCID:PMC11905140

[126] Schneider P,Arentsen-Peters STCJM.Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia.Exp Hematol Oncol2023;12:81 PMCID:PMC10517487

[127] Pinton A,Doublet C.PHF6-altered T-ALL harbor epigenetic repressive switch at bivalent promoters and respond to 5-azacitidine and venetoclax.Clin Cancer Res2024;30:94-105.

[128] Yankova E,Albertella M.Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia.Nature2021;593:597-601 PMCID:PMC7613134

[129] Cheng S,Ying J.20(S)-ginsenoside Rh2 ameliorates ATRA resistance in APL by modulating lactylation-driven METTL3.J Ginseng Res2024;48:298-309 PMCID:PMC11068957

[130] Zhang Y,Wei W.Dysregulation of SIRT3 SUMOylation confers AML chemoresistance via controlling HES1-dependent fatty acid oxidation.Int J Mol Sci2022;23:8282 PMCID:PMC9368767

[131] Maganti HB,Cafariello C.Targeting the MTF2-MDM2 axis sensitizes refractory acute myeloid leukemia to chemotherapy.Cancer Discov2018;8:1376-89 PMCID:PMC7200079

[132] Li J,Shrimp JH.PRC2 inhibitors overcome glucocorticoid resistance driven by NSD2 mutation in pediatric acute lymphoblastic leukemia.Cancer Discov2022;12:186-203

[133] Peirs S,Matthijssens F.Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia.Leukemia2017;31:2037-47

[134] Monteith AJ,Silver AJ.Lactate utilization enables metabolic escape to confer resistance to BET inhibition in acute myeloid leukemia.Cancer Res2024;84:1101-14 PMCID:PMC10984779

[135] Jiang Y,Wang T.AMP-activated protein kinase links acetyl-CoA homeostasis to BRD4 recruitment in acute myeloid leukemia.Blood2019;134:2183-94 PMCID:PMC6908829

[136] Benyoucef A,Cuddihy A.JAK/BCL2 inhibition acts synergistically with LSD1 inhibitors to selectively target ETP-ALL.Leukemia2022;36:2802-16 PMCID:PMC9712096

[137] Boldrin E,Niedermayer A.MicroRNA-497/195 is tumor suppressive and cooperates with CDKN2A/B in pediatric acute lymphoblastic leukemia.Blood2021;138:1953-65

[138] Li X,Ma S.YTHDC1 is a therapeutic target for B-cell acute lymphoblastic leukemia by attenuating DNA damage response through the KMT2C-H3K4me1/me3 epigenetic axis.Leukemia2025;39:308-22

[139] Somers K,Bongers A.Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia.Int J Cancer2020;146:1902-16

[140] Dai B,Wang Y.Targeting HDAC3 to overcome the resistance to ATRA or arsenic in acute promyelocytic leukemia through ubiquitination and degradation of PML-RARα.Cell Death Differ2023;30:1320-33 PMCID:PMC10154408

[141] Mosier DE,Baird SM.Transfer of a functional human immune system to mice with severe combined immunodeficiency.Nature1988;335:256-9

[142] Traggiai E,Mazzucchelli L.Development of a human adaptive immune system in cord blood cell-transplanted mice.Science2004;304:104-7

[143] Chiorazzi M,Krasnick B.Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment.J Immunother Cancer2023;11:e006921 PMCID:PMC10373695

[144] Tyagi A,El-Dana F.Evidence supporting a role for the immune checkpoint protein B7-H3 in NK cell-mediated cytotoxicity against AML.Blood2022;139:2782-96 PMCID:PMC11022957

[145] Ruzicka M,Formisano S.RIG-I-based immunotherapy enhances survival in preclinical AML models and sensitizes AML cells to checkpoint blockade.Leukemia2020;34:1017-26 PMCID:PMC7214254

[146] Mani R,Nunes J.Fc-engineered anti-CD33 monoclonal antibody potentiates cytotoxicity of membrane-bound interleukin-21 expanded natural killer cells in acute myeloid leukemia.Cytotherapy2020;22:369-76 PMCID:PMC8176194

[147] Herbrich S,Cai T.Overexpression of CD200 is a stem cell-specific mechanism of immune evasion in AML.J Immunother Cancer2021;9:e002968 PMCID:PMC8323398

[148] Ho JNHG,Lowinus T.Targeting MDM2 enhances antileukemia immunity after allogeneic transplantation via MHC-II and TRAIL-R1/2 upregulation.Blood2022;140:1167-81 PMCID:PMC9461473

[149] El Khawanky N,Yu W.Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia.Nat Commun2021;12:6436 PMCID:PMC8575966

[150] Rimando JC,Rettig MP.Flotetuzumab and other T-cell immunotherapies upregulate MHC class II expression on acute myeloid leukemia cells.Blood2023;141:1718-23 PMCID:PMC10273090

[151] Augsberger C,Xu W.Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC-specific T-cell bispecific antibody.Blood2021;138:2655-69 PMCID:PMC9037755

[152] Reiter K,Krupka C.Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia.Leukemia2018;32:313-22 PMCID:PMC5808080

[153] Watts B,Evans K.The CD123 antibody-drug conjugate pivekimab sunirine exerts profound activity in preclinical models of pediatric acute lymphoblastic leukemia.Hemasphere2025;9:e70063 PMCID:PMC11739898

[154] Pan J,Deng BP.High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients.Leukemia2017;31:2587-93

[155] Chen GM,Perazzelli J,Barrett DM.Characterization of leukemic resistance to CD19-targeted CAR T-cell therapy through deep genomic sequencing.Cancer Immunol Res2023;11:13-9 PMCID:PMC9808313

[156] Anand P,Dimitrova V.Single-cell RNA-seq reveals developmental plasticity with coexisting oncogenic states and immune evasion programs in ETP-ALL.Blood2021;137:2463-80 PMCID:PMC8109012

[157] Singh N,Shestova O.Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T-cell dysfunction.Cancer Discov2020;10:552-67 PMCID:PMC7416790

[158] Witkowski MT,Evensen NA.Extensive remodeling of the immune microenvironment in B cell acute lymphoblastic leukemia.Cancer Cell2020;37:867-82.e12 PMCID:PMC7341535

[159] Mandal K,Yu C.Structural surfaceomics reveals an AML-specific conformation of integrin β₂ as a CAR T cellular therapy target.Nat Cancer2023;4:1592-609 PMCID:PMC10663162

[160] Ruella M,Kenderian SS.Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies.J Clin Invest2016;126:3814-26 PMCID:PMC5096828

[161] Casirati G,Mucci A.Epitope editing enables targeted immunotherapy of acute myeloid leukaemia.Nature2023;621:404-14 PMCID:PMC10499609

[162] Benmebarek MR,Herrmann M.A modular and controllable T cell therapy platform for acute myeloid leukemia.Leukemia2021;35:2243-57 PMCID:PMC7789085

[163] Loff S,Meyer JE.Rapidly switchable universal CAR-T cells for treatment of CD123-positive leukemia.Mol Ther Oncolytics2020;17:408-20 PMCID:PMC7240059

[164] Ataca Atilla P,Tashiro H.Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia.J Immunother Cancer2020;8:e001229 PMCID:PMC7497527

[165] Ruella M,Shestova O.A cellular antidote to specifically deplete anti-CD19 chimeric antigen receptor-positive cells.Blood2020;135:505-9 PMCID:PMC7019191

[166] Sugita M,Zong H.Allogeneic TCRαβ deficient CAR T-cells targeting CD123 in acute myeloid leukemia.Nat Commun2022;13:2227 PMCID:PMC9050731

[167] Oh BLZ,Coustan-Smith E.Fratricide-resistant CD7-CAR T cells in T-ALL.Nat Med2024;30:3687-96

[168] Wunderlich M,Sexton C.PD-1 inhibition enhances blinatumomab response in a UCB/PDX model of relapsed pediatric B-cell acute lymphoblastic leukemia.Front Oncol2021;11:642466 PMCID:PMC8076590

[169] Kaeding AJ,Gopalakrishnapillai A.Mesothelin is a novel cell surface disease marker and potential therapeutic target in acute myeloid leukemia.Blood Adv2021;5:2350-61 PMCID:PMC8114558

[170] Roas M,Kasper MA.Targeting FLT3 with a new-generation antibody-drug conjugate in combination with kinase inhibitors for treatment of AML.Blood2023;141:1023-35

[171] Ávila Ávila A,Oliveira ML.Targeting the TNF/IAP pathway synergizes with anti-CD3 immunotherapy in T-cell acute lymphoblastic leukemia.Blood2024;143:2166-77 PMCID:PMC11143533

[172] Minuzzo S,Pinazza M.Targeting NOTCH1 in combination with antimetabolite drugs prolongs life span in relapsed pediatric and adult T-acute lymphoblastic leukemia xenografts.Exp Hematol Oncol2023;12:76 PMCID:PMC10476325

[173] Jiménez-Reinoso A,Martinez-Moreno A.Efficient preclinical treatment of cortical T cell acute lymphoblastic leukemia with T lymphocytes secreting anti-CD1a T cell engagers.J Immunother Cancer2022;10:e005333 PMCID:PMC9791403

[174] Balestra T,Bagashev A.Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia.Leukemia2025;39:555-67 PMCID:PMC11879877

[175] Temple WC,Naik A.Framework humanization optimizes potency of anti-CD72 nanobody CAR-T cells for B-cell malignancies.J Immunother Cancer2023;11:e006985 PMCID:PMC10680002

[176] Xu N,Yang L.Priming leukemia with 5-azacytidine enhances CAR T cell therapy.Immunotargets Ther2021;10:123-40 PMCID:PMC8091475

[177] Le Q,Tang T.Therapeutic targeting of mesothelin with chimeric antigen receptor T cells in acute myeloid leukemia.Clin Cancer Res2021;27:5718-30 PMCID:PMC9401532

[178] Lichtman EI,Shou P.Preclinical evaluation of B7-H3-specific chimeric antigen receptor T cells for the treatment of acute myeloid leukemia.Clin Cancer Res2021;27:3141-53 PMCID:PMC8248479

[179] Atar D,Mast AS.Rational combinatorial targeting by adapter CAR-T-cells (AdCAR-T) prevents antigen escape in acute myeloid leukemia.Leukemia2024;38:2183-95 PMCID:PMC11436361

[180] Caruso S,Del Bufalo F.Safe and effective off-the-shelf immunotherapy based on CAR.CD123-NK cells for the treatment of acute myeloid leukaemia.J Hematol Oncol2022;15:163 PMCID:PMC9636687

[181] Mansour AG,Li Z.Off-the-shelf CAR - engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia.Blood Adv2023;7:6225-39 PMCID:PMC10582841

[182] Stuani L,Saland E.Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.J Exp Med2021;218:e20200924 PMCID:PMC7995203

[183] Luo Q,Prado MA.Targetable leukaemia dependency on noncanonical PI3Kγ signalling.Nature2024;630:198-205

[184] Liu Y,Liu J.Uridine metabolism as a targetable metabolic achilles’ heel for chemo-resistant B-ALL.bioRxiv2025; PMCID:PMC11838334

[185] Jin F,Liu Y.Engineered cell membrane vesicles loaded with lysosomophilic drug for acute myeloid leukemia therapy via organ-cell-organelle cascade-targeting.Biomaterials2025;317:123091

[186] Bae KH,Mong J.Bone marrow-targetable green tea catechin-based micellar nanocomplex for synergistic therapy of acute myeloid leukemia.J Nanobiotechnology2022;20:481 PMCID:PMC9670631

[187] Bäumer N,Wittmann L.Electrostatic anti-CD33-antibody-protamine nanocarriers as platform for a targeted treatment of acute myeloid leukemia.J Hematol Oncol2022;15:171 PMCID:PMC9716776

[188] Kong T,Yang K.DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression.Nat Cancer2023;4:108-27 PMCID:PMC11288645

[189] Cartel M,Gotanègre M.Inhibition of ubiquitin-specific protease 7 sensitizes acute myeloid leukemia to chemotherapy.Leukemia2021;35:417-32 PMCID:PMC7245510

[190] Geisslinger F,Chao YK,Vollmar AM.Targeting TPC2 sensitizes acute lymphoblastic leukemia cells to chemotherapeutics by impairing lysosomal function.Cell Death Dis2022;13:668 PMCID:PMC9343397

[191] Salik B,Hassan N.Targeting RSPO3-LGR4 signaling for leukemia stem cell eradication in acute myeloid leukemia.Cancer Cell2020;38:263-78.e6

[192] Surka C,Mbong N.CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells.Blood2021;137:661-77 PMCID:PMC8215192

[193] Cunningham A,Alshamleh I.Dietary methionine starvation impairs acute myeloid leukemia progression.Blood2022;140:2037-52

[194] Bruedigam C,Song A.Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.Nat Cancer2024;5:47-65 PMCID:PMC10824665

[195] Lin KH,Xie A.P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.Nat Cancer2022;3:837-51 PMCID:PMC9949365