Rheingold SR, Bhojwani D, Ji L, Xu X, Devidas M, Kairalla JA, et al. Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children’s Oncology Group study. Leukemia. 2024;38:2382–94.
Google Scholar
Sancho J-M, Ribera J-M, Oriol A, Hernandez-Rivas J-M, Rivas C, Bethencourt C, et al. Central nervous system recurrence in adult patients with acute lymphoblastic leukemia. Cancer. 2006;106:2540–6.
Google Scholar
Reman O, Pigneux A, Huguet F, Vey N, Delannoy A, Fegueux N, et al. Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis and/or at first relapse: results from the GET-LALA group. Leuk Res. 2008;32:1741–50.
Google Scholar
Lazarus HM, Richards SM, Chopra R, Litzow MR, Burnett AK, Wiernik PH, et al. Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis: results from the international ALL trial MRC UKALL XII/ECOG E2993. Blood. 2006;108:465–72.
Google Scholar
Dargenio M, Bonifacio M, Chiaretti S, Vitale A, Fracchiolla NS, Papayannidis C, et al. Incidence, treatment and outcome of central nervous system relapse in adult acute lymphoblastic leukaemia patients treated front-line with paediatric-inspired regimens: A retrospective multicentre Campus ALL study. Br J Haematol. 2023;200:440–50.
Google Scholar
Pauls S, Fischer A-C, Brambs H-J, Fetscher S, Höche W, Bommer M. Use of magnetic resonance imaging to detect neoplastic meningitis: limited use in leukemia and lymphoma but convincing results in solid tumors. Eur J Radiol. 2012;81:974–8.
Google Scholar
Gorchynski J, Oman J, Newton T. Interpretation of traumatic lumbar punctures in the setting of possible subarachnoid hemorrhage: who can be safely discharged? Cal J Emerg Med. 2007;8:3–7.
Google Scholar
Gajjar A, Harrison PL, Sandlund JT, Rivera GK, Ribeiro RC, Rubnitz JE, et al. Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood. 2000;96:3381–4.
Google Scholar
Del Principe MI, Buzzatti E, Piciocchi A, Forghieri F, Bonifacio M, Lessi F, et al. Clinical significance of occult central nervous system disease in adult acute lymphoblastic leukemia. A multicenter report from the Campus ALL Network. Haematologica. 2021;106:39–45.
Google Scholar
Maloney KW, Devidas M, Wang C, Mattano LA, Friedmann AM, Buckley P, et al. Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: results of Children’s Oncology Group Trial AALL0331. J Clin Oncol. 2020;38:602–12.
Google Scholar
de Haas V, Pieters R, van der Sluijs-Gelling AJ, Zwaan CM, de Groot-Kruseman HA, Sonneveld E, et al. Flowcytometric evaluation of cerebrospinal fluid in childhood ALL identifies CNS involvement better then conventional cytomorphology. Leukemia. 2021;35:1773–6.
Google Scholar
Rodriguez A, Wengyn M, Vu MH, Doan A, Raca G, Bhojwani D, et al. Impact of central nervous system (CNS) leukemia status-based therapeutic protocol change on the incidence of CNS2 diagnosis in pediatric B-lymphoblastic acute leukemia. Blood. 2023;142:1457.
Google Scholar
Thastrup M, Marquart HV, Schmiegelow K. Flow cytometric detection of malignant blasts in cerebrospinal fluid: a biomarker of central nervous system involvement in childhood acute lymphoblastic leukemia. Biomolecules. 2022;12:813.
Google Scholar
Winick N, Devidas M, Chen S, Maloney K, Larsen E, Mattano L, et al. Impact of initial CSF findings on outcome among patients with national cancer institute standard- and high-risk B-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group. J Clin Oncol. 2017;35:2527–34.
Google Scholar
Bürger B, Zimmermann M, Mann G, Kühl J, Löning L, Riehm H, et al. Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol. 2003;21:184–8.
Google Scholar
Schwab RS, Weiss S. The neurologic aspect of leukemia. Am J Med Sci. 1935;189:766–77.
Google Scholar
Evans AE, Gilbert ES, Zandstra R. The increasing incidence of central nervous system leukemia in children. (Children’s cancer study group a). Cancer. 1970;26:404–9.
Google Scholar
Mahmoud HH, Rivera GK, Hancock ML, Krance RA, Kun LE, Behm FG, et al. Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med. 1993;329:314–9.
Google Scholar
Sampathi S, Chernyavskaya Y, Haney MG, Moore LH, Snyder IA, Cox AH, et al. Nanopore sequencing of clonal IGH rearrangements in cell-free DNA as a biomarker for acute lymphoblastic leukemia. Front Oncol. 2022;ume 12:2022.
Arthur C, Rezayee F, Mogensen N, Saft L, Rosenquist R, Nordenskjöld M, et al. Patient-specific assays based on whole-genome sequencing data to measure residual disease in children with acute lymphoblastic leukemia: a proof of concept study. Front Oncol. 2022;ume 12:2022.
Milán Salvatierra AI, Bravata Alcántara JC, Alvarado Castro VM, Plascencia Nieto ES, Cruz Leyto F, Tejeda Romero M, et al. CD79A and IL7R mRNA levels in the cerebrospinal fluid of adults with acute B-cell lymphoblastic leukemia: a pilot study. Diseases. 2025;13:206.
Google Scholar
Péterffy B, Nádasi TJ, Krizsán S, Horváth A, Márk Á, Barna G, et al. Digital PCR-based quantification of miR-181a in the cerebrospinal fluid aids patient stratification in pediatric acute lymphoblastic leukemia. Sci Rep. 2024;14:28556.
Google Scholar
Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood. 2003;101:3809–17.
Google Scholar
Salzer WL, Burke MJ, Devidas M, Dai Y, Hardy KK, Kairalla JA, et al. Impact of intrathecal triple therapy versus intrathecal methotrexate on disease-free survival for high-risk B-lymphoblastic leukemia: Children’s Oncology Group Study AALL1131. J Clin Oncol. 2020;38:2628–38.
Google Scholar
Muldoon LL, Soussain C, Jahnke K, Johanson C, Siegal T, Smith QR, et al. Chemotherapy delivery issues in central nervous system malignancy: a reality check. J Clin Oncol. 2007;25:2295–305.
Google Scholar
Cortes J, O’Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995;86:2091–7.
Google Scholar
Gottschalk Højfeldt S, Grell K, Abrahamsson J, Lund B, Vettenranta K, Jónsson ÓG, et al. Relapse risk following truncation of pegylated asparaginase in childhood acute lymphoblastic leukemia. Blood. 2021;137:2373–82.
Google Scholar
Rizzari C, Lanvers-Kaminsky C, Valsecchi MG, Ballerini A, Matteo C, Gerss J, et al. Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study. Haematologica. 2019;104:1812–21.
Google Scholar
Balis FM, Poplack DG. Central nervous system pharmacology of antileukemic drugs. J Pediatr Hematol/Oncol. 1989;11:74–86.
Google Scholar
Bleyer WA, Drake JC, Chabner BA. Neurotoxicity and elevated cerebrospinal-fluid methotrexate concentration in meningeal leukemia. N Engl J Med. 1973;289:770–3.
Google Scholar
Byrnes DM, Vargas F, Dermarkarian C, Kahn R, Kwon D, Hurley J, et al. Complications of intrathecal chemotherapy in adults: single-institution experience in 109 consecutive patients. J Oncol. 2019;2019:4047617.
Google Scholar
Schuitema I, Deprez S, Van Hecke W, Daams M, Uyttebroeck A, Sunaert S, et al. Accelerated aging, decreased white matter integrity, and associated neuropsychological dysfunction 25 years after pediatric lymphoid malignancies. J Clin Oncol. 2013;31:3378–88.
Google Scholar
Iyer NS, Balsamo LM, Bracken MB, Kadan-Lottick NS. Chemotherapy-only treatment effects on long-term neurocognitive functioning in childhood ALL survivors: a review and meta-analysis. Blood. 2015;126:346–53.
Google Scholar
Anastasopoulou S, Nielsen RL, Als-Nielsen B, Banerjee J, Eriksson MA, Helenius M, et al. Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: phenotypes, risk factors and genotypes. Haematologica. 2022;107:2318–28.
Google Scholar
Heilmann J, Vieth S, Möricke A, Attarbaschi A, Barbaric D, Bodmer N, et al. Effect of two additional doses of intrathecal methotrexate during induction therapy on serious infectious toxicity in pediatric patients with acute lymphoblastic leukemia. Haematologica. 2023;108:3278–86.
Google Scholar
Williams MTS, Yousafzai YM, Elder A, Rehe K, Bomken S, Frishman-Levy L, et al. The ability to cross the blood–cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts. Blood. 2016;127:1998–2006.
Google Scholar
Bartram J, Goulden N, Wright G, Adams S, Brooks T, Edwards D, et al. High throughput sequencing in acute lymphoblastic leukemia reveals clonal architecture of central nervous system and bone marrow compartments. Haematologica. 2018;103:e110–e4.
Google Scholar
Vanner RJ, Dobson SM, Gan OI, McLeod J, Schoof EM, Grandal I, et al. Multiomic profiling of central nervous system leukemia identifies mRNA translation as a therapeutic target. Blood Cancer Discov. 2022;3:16–31.
Google Scholar
Yao H, Price TT, Cantelli G, Ngo B, Warner MJ, Olivere L, et al. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature. 2018;560:55–60.
Google Scholar
Rajakumar SA, Grandal I, Minden MD, Hitzler JK, Guidos CJ, Danska JS. Targeted blockade of immune mechanisms inhibit B precursor acute lymphoblastic leukemia cell invasion of the central nervous system. Cell Rep Med. 2021;2:100470.
Google Scholar
Kato I, Nishinaka Y, Nakamura M, Akarca AU, Niwa A, Ozawa H, et al. Hypoxic adaptation of leukemic cells infiltrating the CNS affords a therapeutic strategy targeting VEGFA. Blood. 2017;129:3126–9.
Google Scholar
Savino AM, Fernandes SI, Olivares O, Zemlyansky A, Cousins A, Markert EK, et al. Metabolic adaptation of acute lymphoblastic leukemia to the central nervous system microenvironment is dependent on Stearoyl CoA desaturase. Nat Cancer. 2020;1:998–1009.
Google Scholar
Cousins A, Olivares O, Markert E, Manoharan A, Bubnova X, Bresolin S, et al. Central nervous system involvement in childhood acute lymphoblastic leukemia is linked to upregulation of cholesterol biosynthetic pathways. Leukemia. 2022;36:2903–7.
Google Scholar
Akers SM, Rellick SL, Fortney JE, Gibson LF. Cellular elements of the subarachnoid space promote ALL survival during chemotherapy. Leuk Res. 2011;35:705–11.
Google Scholar
Fernández-Sevilla LM, Valencia J, Flores-Villalobos MA, Gonzalez-Murillo Á, Sacedón R, Jiménez E, et al. The choroid plexus stroma constitutes a sanctuary for paediatric B-cell precursor acute lymphoblastic leukaemia in the central nervous system. J Pathol. 2020;252:189–200.
Google Scholar
Sharma ND, Keewan EA, Ornatowski W, Nysus M, Paul S, Jacquez Q, et al. CXCR3/CXCL10 signaling pathway drives T-ALL into the CNS/meningeal microenvironment. Blood. 2023;142:37.
Google Scholar
Jonart LM, Ostergaard J, Brooks A, Fitzpatrick G, Chen L, Gordon PM. CXCR4 antagonists disrupt leukaemia-meningeal cell adhesion and attenuate chemoresistance. Br J Haematol. 2023;201:459–69.
Google Scholar
Jonart LM, Ebadi M, Basile P, Johnson K, Makori J, Gordon PM. Disrupting the leukemia niche in the central nervous system attenuates leukemia chemoresistance. Haematologica. 2020;105:2130–40.
Google Scholar
Kang J, Ostergaard J, Wang X, Gordon PM. Cerebrospinal fluid attenuates the efficacy of methotrexate against acute lymphoblastic leukemia cells. Blood Neoplasia. 2025;2:100057.
Google Scholar
Basile P, Jonart LM, Ebadi M, Johnson K, Kerfeld M, Gordon PM. The meninges enhance leukaemia survival in cerebral spinal fluid. Br J Haematol. 2020;189:513–7.
Google Scholar
Frishman-Levy L, Izraeli S. Advances in understanding the pathogenesis of CNS acute lymphoblastic leukaemia and potential for therapy. Br J Haematol. 2017;176:157–67.
Google Scholar
Price RA. Histopathology of CNS leukemia and complications of therapy. J Pediatr Hematol/Oncol. 1979;1:21–30.
Google Scholar
Spector R, Robert Snodgrass S, Johanson CE. A balanced view of the cerebrospinal fluid composition and functions: focus on adult humans. Exp Neurol. 2015;273:57–68.
Google Scholar
Remsik J, Boire A. The path to leptomeningeal metastasis. Nat Rev Cancer. 2024;24:448–60.
Google Scholar
Shechter R, London A, Schwartz M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat Rev Immunol. 2013;13:206–18.
Google Scholar
Jost TR, Borga C, Radaelli E, Romagnani A, Perruzza L, Omodho L, et al. Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia. J Leukoc Biol. 2016;99:1077–87.
Google Scholar
Provencio JJ, Kivisäkk P, Tucky BH, Luciano MG, Ransohoff RM. Comparison of ventricular and lumbar cerebrospinal fluid T cells in non-inflammatory neurological disorder (NIND) patients. J Neuroimmunol. 2005;163:179–84.
Google Scholar
Kivisäkk P, Mahad DJ, Callahan MK, Sikora K, Trebst C, Tucky B, et al. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann Neurol. 2004;55:627–38.
Google Scholar
Lalor SJ, Segal BM. Lymphoid chemokines in the CNS. J Neuroimmunol. 2010;224:56–61.
Google Scholar
Eisa-Beygi S, Arulsamy K, Cui K, Wu H, Wang B, Chen K, et al. The chemokine receptor CXCR4 and its ligand CXCL12 (SDF-1) localize to ependymal cilia in brain ventricles. Vasc Pharmacol. 2025;161:107546.
Google Scholar
Kivisäkk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci USA. 2003;100:8389–94.
Google Scholar
Kearns NA, Iatrou A, Flood DJ, De Tissera S, Mullaney ZM, Xu J, et al. Dissecting the human leptomeninges at single-cell resolution. Nat Commun. 2023;14:7036.
Google Scholar
Cardona CI, Rodriguez A, Torres VC, Sanchez A, Torres A, Vazquez AE, et al. C-C chemokine receptor 7 promotes T-cell acute lymphoblastic leukemia invasion of the central nervous system via β2-integrins. Int J Mol Sci. 2024;25:9649.
Google Scholar
März M, Meyer S, Erb U, Georgikou C, Horstmann MA, Hetjens S, et al. Pediatric acute lymphoblastic leukemia—conquering the CNS across the choroid plexus. Leuk Res. 2018;71:47–54.
Google Scholar
Buonamici S, Trimarchi T, Ruocco MG, Reavie L, Cathelin S, Mar BG, et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature. 2009;459:1000–4.
Google Scholar
Krumbholz M, Theil D, Steinmeyer F, Cepok S, Hemmer B, Hofbauer M, et al. CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions. J Neuroimmunol. 2007;190:72–9.
Google Scholar
Jaime-Pérez JC, Gamboa-Alonso CM, Jiménez-Castillo RA, López-Silva LJ, Pinzón-Uresti MA, Gómez-De León A, et al. TNF-α increases in the CSF of children with acute lymphoblastic leukemia before CNS relapse. Blood Cells, Molecules Dis. 2017;63:27–31.
Google Scholar
Rajakumar SA, Papp E, Lee KK, Grandal I, Merico D, Liu CC, et al. B cell acute lymphoblastic leukemia cells mediate RANK-RANKL–dependent bone destruction. Sci Transl Med. 2020;12:eaba5942.
Google Scholar
Brioschi S, Wang WL, Peng V, Wang M, Shchukina I, Greenberg ZJ, et al. Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders. Science. 2021;373:eabf9277.
Google Scholar
Mazzitelli JA, Pulous FE, Smyth LCD, Kaya Z, Rustenhoven J, Moskowitz MA, et al. Skull bone marrow channels as immune gateways to the central nervous system. Nat Neurosci. 2023;26:2052–62.
Google Scholar
Liu L, Zhang X, Chai Y, Zhang J, Deng Q, Chen X. Skull bone marrow and skull meninges channels: redefining the landscape of central nervous system immune surveillance. Cell Death Dis. 2025;16:53.
Google Scholar
Quinlan L, Page EC, Rehn J, McClure BJ, Osborn MP, Moore AS, et al. High expression of NTRK1 in ETV6::RUNX1 positive acute lymphoblastic leukaemia drives factor independence and sensitivity to larotrectinib. Pediatr Blood Cancer. 2025;72:e31983.
Google Scholar
Yoshida K, Gage FH. Fibroblast growth factors stimulate nerve growth factor synthesis and secretion by astrocytes. Brain Res. 1991;538:118–26.
Google Scholar
Sharma ND, Keewan EA, Ornatowski W, Paul S, Nysus M, Barnett CC, et al. T cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges. J Clin Investig. 2025;136:e188888.
Google Scholar
Gang EJ, Kim HN, Hsieh Y-T, Ruan Y, Ogana HA, Lee S, et al. Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia. Blood. 2020;136:210–23.
Google Scholar
Ridge S, Yao H, Price TT, Whiteley AE, Burns M, Sipkins DA. PI3Kα/δ inhibitor, copanlisib, inhibits acute lymphoblastic leukemia cell growth, increases survival and inhibits CNS disease progression in leukemic mice. Blood. 2019;134:2758.
Google Scholar
Hu W, Wang X, Yang R, Bi L, Xie Y, Zhang Z, et al. Expression of CD56 is a risk factor for acute lymphocytic leukemia with central nervous system involvement in adults. Hematology. 2017;22:81–7.
Google Scholar
Harjunpää H, Llort Asens M, Guenther C, Fagerholm SC. Cell adhesion molecules and their roles and regulation in the immune and tumor microenvironment. Front Immunol. 2019;10:1078.
Google Scholar
Gómez AM, Martínez C, González M, Luque A, Melen GJ, Martínez J, et al. Chemokines and relapses in childhood acute lymphoblastic leukemia: a role in migration and in resistance to antileukemic drugs. Blood Cells, Molecules, Dis. 2015;55:220–7.
Google Scholar
Shen W, Bendall LJ, Gottlieb DJ, Bradstock KF. The chemokine receptor CXCR4 enhances integrin-mediated in vitro adhesion and facilitates engraftment of leukemic precursor-B cells in the bone marrow. Exp Hematol. 2001;29:1439–47.
Google Scholar
Liu T, Zhang L, Joo D, Sun S-C. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023.
Google Scholar
Shabnam S, Jana H, Renate K-S, Lorenz B, Cornelia E, Javier P, et al. High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse. Haematologica. 2011;96:1627–35.
Google Scholar
Hsieh Y-T, Gang EJ, Geng H, Park E, Huantes S, Chudziak D, et al. Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy. Blood. 2013;121:1814–8.
Google Scholar
Winter SS, Sweatman JJ, Lawrence MB, Rhoades TH, Hart AL, Larson RS. Enhanced T-lineage acute lymphoblastic leukaemia cell survival on bone marrow stroma requires involvement of LFA-1 and ICAM-1. Br J Haematol. 2001;115:862–71.
Google Scholar
Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A, et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med. 2003;9:1158–65.
Google Scholar
Enlund S, Sinha I, Neofytou C, Amor AR, Papadakis K, Nilsson A, et al. The CNS microenvironment promotes leukemia cell survival by disrupting tumor suppression and cell cycle regulation in pediatric T-cell acute lymphoblastic leukemia. Exp Cell Res. 2024;437:114015.
Google Scholar
Panka DJ, Mano T, Suhara T, Walsh K, Mier JW. Phosphatidylinositol 3-Kinase/Akt Activity Regulates c-FLIP Expression in Tumor Cells*. J Biol Chem. 2001;276:6893–6.
Google Scholar
Kennedy SG, Kandel ES, Cross TK, Hay N. Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol. 1999;19:5800–10.
Google Scholar
Zhou H, Li XM, Meinkoth J, Pittman RN. Akt regulates cell survival and apoptosis at a postmitochondrial level. J Cell Biol. 2000;151:483–94.
Google Scholar
Jing D, Bhadri VA, Beck D, Thoms JAI, Yakob NA, Wong JWH, et al. Opposing regulation of BIM and BCL2 controls glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells. Blood. 2015;125:273–83.
Google Scholar
Edward L, Theocharis P, Katja P, Eva B, Martin C, Stefan S, et al. Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members. Haematologica. 2007;92:1460–9.
Google Scholar
Zhou M, Gu L, Abshire TC, Homans A, Billett AL, Yeager AM, et al. Incidence and prognostic significance of MDM2 oncoprotein overexpression in relapsed childhood acute lymphoblastic leukemia. Leukemia. 2000;14:61–7.
Google Scholar
Aubrey BJ, Kelly GL, Janic A, Herold MJ, Strasser A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. 2018;25:104–13.
Google Scholar
Kracikova M, Akiri G, George A, Sachidanandam R, Aaronson SA. A threshold mechanism mediates p53 cell fate decision between growth arrest and apoptosis. Cell Death Differ. 2013;20:576–88.
Google Scholar
Raz S, Sheban D, Gonen N, Stark M, Berman B, Assaraf YG. Severe hypoxia induces complete antifolate resistance in carcinoma cells due to cell cycle arrest. Cell Death Dis. 2014;5:e1067 -e.
Google Scholar
Remsik J, Chi Y, Tong X, Sener U, Derderian C, Park A, et al. Leptomeningeal metastatic cells adopt two phenotypic states. Cancer Rep. 2022;5:e1236.
Google Scholar
Münch V, Trentin L, Herzig J, Demir S, Seyfried F, Kraus JM, et al. Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor. Blood. 2017;130:643–54.
Google Scholar
Jaakkola P, Mole DR, Tian Y-M, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292:468–72.
Google Scholar
Zhang X, Saarinen AM, Hitosugi T, Wang Z, Wang L, Ho TH, et al. Inhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia. eLife. 2017;6:e31132.
Google Scholar
Munir R, Lisec J, Swinnen JV, Zaidi N. Lipid metabolism in cancer cells under metabolic stress. Br J Cancer. 2019;120:1090–8.
Google Scholar
Cacho-Díaz B, Lorenzana-Mendoza NA, Reyes-Soto G, Hernández-Estrada A, Monroy-Sosa A, Guraieb-Chahin P, et al. Lactate dehydrogenase as a prognostic marker in neoplastic meningitis. J Clin Neurosci. 2018;51:39–42.
Google Scholar
Herrlinger U, Förschler H, Küker W, Meyermann R, Bamberg M, Dichgans J, et al. Leptomeningeal metastasis: survival and prognostic factors in 155 patients. J Neurol Sci. 2004;223:167–78.
Google Scholar
Schlaepfer IR, Nambiar DK, Ramteke A, Kumar R, Dhar D, Agarwal C, et al. Hypoxia induces triglycerides accumulation in prostate cancer cells and extracellular vesicles supporting growth and invasiveness following reoxygenation. Oncotarget. 2015;6:22836–56.
Google Scholar
Rysman E, Brusselmans K, Scheys K, Timmermans L, Derua R, Munck S, et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res. 2010;70:8117–26.
Google Scholar
Wang X, Sato R, Brown MS, Hua X, Goldstein JL. SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell. 1994;77:53–62.
Google Scholar
Lewis CA, Brault C, Peck B, Bensaad K, Griffiths B, Mitter R, et al. SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme. Oncogene. 2015;34:5128–40.
Google Scholar
Melana JP, Mignolli F, Stoyanoff T, Aguirre MV, Balboa MA, Balsinde J, et al. The hypoxic microenvironment induces stearoyl-CoA desaturase-1 overexpression and lipidomic profile changes in clear cell renal cell carcinoma. Cancers. 2021;13:2962.
Google Scholar
Qiu B, Ackerman D, Sanchez DJ, Li B, Ochocki JD, Grazioli A, et al. HIF2α-dependent lipid storage promotes endoplasmic reticulum homeostasis in clear-cell renal cell carcinoma. Cancer Discov. 2015;5:652–67.
Google Scholar
Du W, Zhang L, Brett-Morris A, Aguila B, Kerner J, Hoppel CL, et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat Commun. 2017;8:1769.
Google Scholar
Gao X, Lin S-H, Ren F, Li J-T, Chen J-J, Yao C-B, et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat Commun. 2016;7:11960.
Google Scholar
Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell. 2015;27:57–71.
Google Scholar
Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2012;481:380–4.
Google Scholar
Wise DR, Ward PS, Shay JES, Cross JR, Gruber JJ, Sachdeva UM, et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci USA. 2011;108:19611–6.
Google Scholar
Chen Z, Han F, Du Y, Shi H, Zhou W. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023;8:70.
Google Scholar
Chapp AD, Schum S, Behnke JE, Hahka T, Huber MJ, Jiang E, et al. Measurement of cations, anions, and acetate in serum, urine, cerebrospinal fluid, and tissue by ion chromatography. Physiol Rep. 2018;6:e13666.
Google Scholar
McGale EHF, Pye IF, Stonier C, Hutchinson EC, Aber GM. Studies of the inter-relationship between cerebrospinal fluid and plasma amino acid concentrations in normal individuals. J Neurochem. 1977;29:291–7.
Google Scholar
Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang X-Y, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci. 2008;105:18782–7.
Google Scholar
Yoo HC, Park SJ, Nam M, Kang J, Kim K, Yeo JH, et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab. 2020;31:267–83.e12.
Google Scholar
Gordan JD, Bertout JA, Hu C-J, Diehl JA, Simon MC. HIF-2α promotes hypoxic cell proliferation by enhancing c-Myc transcriptional activity. Cancer Cell. 2007;11:335–47.
Google Scholar
Yoo HC, Yu YC, Sung Y, Han JM. Glutamine reliance in cell metabolism. Exp Mol Med. 2020;52:1496–516.
Google Scholar
Mullen AR, Wheaton WW, Jin ES, Chen P-H, Sullivan LB, Cheng T, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2012;481:385–8.
Google Scholar
Daniëls VW, Smans K, Royaux I, Chypre M, Swinnen JV, Zaidi N. Cancer cells differentially activate and thrive on de novo lipid synthesis pathways in a low-lipid environment. PLOS ONE. 2014;9:e106913.
Google Scholar
Liu X, Cooper DE, Cluntun AA, Warmoes MO, Zhao S, Reid MA, et al. Acetate production from glucose and coupling to mitochondrial metabolism in mammals. Cell. 2018;175:502–13.e13.
Google Scholar
Yoshii Y, Furukawa T, Yoshii H, Mori T, Kiyono Y, Waki A, et al. Cytosolic acetyl-CoA synthetase affected tumor cell survival under hypoxia: the possible function in tumor acetyl-CoA/acetate metabolism. Cancer Sci. 2009;100:821–7.
Google Scholar
Cho HR, Wen H, Ryu YJ, An YJ, Kim HC, Moon WK, et al. An NMR metabolomics approach for the diagnosis of leptomeningeal carcinomatosis. Cancer Res. 2012;72:5179–87.
Google Scholar
Ferro S, Azevedo-Silva J, Casal M, Côrte-Real M, Baltazar F, Preto A. Characterization of acetate transport in colorectal cancer cells and potential therapeutic implications. Oncotarget. 2016;7:70639–53.
Google Scholar
Mochmann LH, Treue D, Bockmayr M, Silva P, Zasada C, Mastrobuoni G, et al. Proteomic profiling reveals ACSS2 facilitating metabolic support in acute myeloid leukemia. Cancer Gene Ther. 2024;31:1344–56.
Google Scholar
Zhang W, Trachootham D, Liu J, Chen G, Pelicano H, Garcia-Prieto C, et al. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nat Cell Biol. 2012;14:276–86.
Google Scholar
Iwamoto S, Mihara K, Downing JR, Pui C-H, Campana D. Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. J Clin Investig. 2007;117:1049–57.
Google Scholar
Chen J, Luo J, Liu Y, Zhou J, Cui H, Deng L. GPS2 confers l-asparaginase resistance in acute lymphoblastic leukemia cells through ATF4/ASNS axis. Carcinogenesis. 2025;46:bgaf035.
Google Scholar
Hoy AJ, Nagarajan SR, Butler LM. Tumour fatty acid metabolism in the context of therapy resistance and obesity. Nat Rev Cancer. 2021;21:753–66.
Google Scholar
Lv Y, Shan Z, Jinzhu H, Likang Z, Zixin Y, Zhao L. Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer. OncoTargets Ther. 2015;8:1941–8.
Google Scholar
Wang K, Zhu X, Zhang K, Yin Y, Chen Y, Zhang T. Interleukin-6 contributes to chemoresistance in MDA-MB-231 cells via targeting HIF-1α. J Biochem Mol Toxicol. 2018;32:e22039.
Google Scholar
Pinzón-Daza ML, Cuellar-Saenz Y, Nualart F, Ondo-Mendez A, Del Riesgo L, Castillo-Rivera F, et al. Oxidative Stress Promotes Doxorubicin-Induced Pgp and BCRP Expression in Colon Cancer Cells Under Hypoxic Conditions. J Cell Biochem. 2017;118:1868–78.
Google Scholar
Xiu B, Zhang W, Huang B, Chen J, Lu H, Fu J, et al. Genetic inhibition of vascular endothelial growth factor receptor-1 significantly inhibits the migration and proliferation of leukemia cells and increases their sensitivity to chemotherapy. Oncol Rep. 2013;29:2030–8.
Google Scholar
Gebing P, Loizou S, Hänsch S, Schliehe-Diecks J, Spory L, Stachura P, et al. A brain organoid/ALL co-culture model reveals the AP-1 pathway as critically associated with CNS involvement of BCP-ALL. Blood Adv. 2024;8:4997–5011.
Google Scholar
Laderoute KR, Calaoagan JM, Gustafson-Brown C, Knapp AM, Li GC, Mendonca HL, et al. The response of c-jun/AP-1 to chronic hypoxia is hypoxia-inducible factor 1 alpha dependent. Mol Cell Biol. 2002;22:2515–23.
Google Scholar
Wang Y, Wan GH, Wu YM, Wang HS, Wang HF, Zhang G, et al. AP-1 confers resistance to anti-cancer therapy by activating XIAP. Oncotarget. 2018;9:14124–37.
Google Scholar
Li YC, Park MJ, Ye S-K, Kim C-W, Kim Y-N. Elevated levels of cholesterol-rich lipid rafts in cancer cells are correlated with apoptosis sensitivity induced by cholesterol-depleting agents. Am J Pathol. 2006;168:1107–18.
Google Scholar
Pardridge WM. The blood-brain barrier: Bottleneck in brain drug development. NeuroRX. 2005;2:3–14.
Google Scholar
Gupta S, Rau RE, Kairalla JA, Rabin KR, Wang C, Angiolillo AL, et al. Blinatumomab in standard-risk B-cell acute lymphoblastic leukemia in children. N Engl J Med. 2025;392:875–91.
Google Scholar
Greenwood M, Gangatharan S, Osborn M, Ng AP, Fleming S, Fedele P, et al. Blinatumomab in de novo AYA ALL-Results of the Australasian Leukaemia and Lymphoma Group ALL09 “SUBLIME” study. Hemasphere. 2026;10:e70291.
Google Scholar
Oh BLZ, Vinanica N, Wong DMH, Campana D. Chimeric antigen receptor T-cell therapy for T-cell acute lymphoblastic leukemia. Haematologica. 2024;109:1677–88.
Google Scholar
He X, Xiao X, Li Q, Jiang Y, Cao Y, Sun R, et al. Anti-CD19 CAR-T as a feasible and safe treatment against central nervous system leukemia after intrathecal chemotherapy in adults with relapsed or refractory B-ALL. Leukemia. 2019;33:2102–4.
Google Scholar
Qi Y, Zhao M, Hu Y, Wang Y, Li P, Cao J, et al. Efficacy and safety of CD19-specific CAR T cell–based therapy in B-cell acute lymphoblastic leukemia patients with CNSL. Blood. 2022;139:3376–86.
Google Scholar
de Gooijer MC, Zhang P, Buil LCM, Çitirikkaya CH, Thota N, Beijnen JH, et al. Buparlisib is a brain penetrable pan-PI3K inhibitor. Sci Rep. 2018;8:10784.
Google Scholar
de Gooijer MC, Zhang P, Weijer R, Buil LCM, Beijnen JH, van Tellingen O. The impact of P-glycoprotein and breast cancer resistance protein on the brain pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors. Int J Cancer. 2018;142:381–91.
Google Scholar
Esquea EM, Ciraku L, Young RG, Merzy J, Talarico AN, Ahmed NN, et al. Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells. Front Pharmacol. 2024;15:1394685.
Google Scholar
Dewdney B, Jenkins MR, Best SA, Freytag S, Prasad K, Holst J, et al. From signalling pathways to targeted therapies: unravelling glioblastoma’s secrets and harnessing two decades of progress. Signal Transduct Target Ther. 2023;8:400.
Google Scholar
Yao H, Price T, Olivere L, Warner M, Tannheimer S, Sipkins DA. PI3Kδ inhibition suppresses central nervous system involvement of acute lymphoblastic leukemia. Blood. 2016;128:282.
Google Scholar
Tolaney SM, Sahebjam S, Le Rhun E, Bachelot T, Kabos P, Awada A, et al. A phase II study of abemaciclib in patients with brain metastases secondary to hormone receptor-positive breast cancer. Clin Cancer Res. 2020;26:5310–9.
Google Scholar
Naz S, Sowers A, Choudhuri R, Wissler M, Gamson J, Mathias A, et al. Abemaciclib, a selective CDK4/6 inhibitor, enhances the radiosensitivity of non-small cell lung cancer in vitro and in vivo. Clin Cancer Res. 2018;24:3994–4005.
Google Scholar
Mohlin S, Hamidian A, von Stedingk K, Bridges E, Wigerup C, Bexell D, et al. PI3K–mTORC2 but not PI3K–mTORC1 Regulates Transcription of HIF2A/EPAS1 and Vascularization in Neuroblastoma. Cancer Res. 2015;75:4617–28.
Google Scholar
Fallah J, Brave MH, Weinstock C, Mehta GU, Bradford D, Gittleman H, et al. FDA approval summary: belzutifan for von Hippel-Lindau disease-associated tumors. Clin Cancer Res. 2022;28:4843–8.
Google Scholar
Cai J, Ye Z, Hu Y, Ye L, Gao L, Wang Y, et al. Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. Cell Death Dis. 2023;14:211.
Google Scholar
Yin F, Yang J, Luo H, Yu T, Lu W, Zhao M, et al. Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids. Cell Death Dis. 2025;16:327.
Google Scholar
Samuels AL, Beesley AH, Yadav BD, Papa RA, Sutton R, Anderson D, et al. A pre-clinical model of resistance to induction therapy in pediatric acute lymphoblastic leukemia. Blood Cancer J. 2014;4:e232. -e.
Google Scholar
Shepardson NE, Shankar GM, Selkoe DJ. Cholesterol level and statin use in Alzheimer disease: II. Review of human trials and recommendations. Arch Neurol. 2011;68:1385–92.
Google Scholar
Montaño A, Forero-Castro M, Marchena-Mendoza D, Benito R, Hernández-Rivas JM. New challenges in targeting signaling pathways in acute lymphoblastic leukemia by NGS approaches: an update. Cancers. 2018;10:110.
Google Scholar
Tasian SK, Hunger SP. Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics. Br J Haematol. 2017;176:867–82.
Google Scholar
Irving J, Matheson E, Minto L, Blair H, Case M, Halsey C, et al. Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition. Blood. 2014;124:3420–30.
Google Scholar
Grommes C, Gavrilovic I, Miller AM, Stone JB, Kaley T, Madzsar JT, et al. Phase Ib of copanlisib in combination with ibrutinib in recurrent/refractory primary CNS lymphoma (PCNSL). Blood. 2019;134:1598.
Google Scholar
Campagne O, Yeo KK, Fangusaro J, Stewart CF. Clinical pharmacokinetics and pharmacodynamics of selumetinib. Clin Pharmacokinetics. 2021;60:283–303.
Google Scholar
Fangusaro J, Onar-Thomas A, Young Poussaint T, Lensing S, Ligon AH, Lindeman N, et al. A phase 2 PBTC study of selumetinib for recurrent/progressive pediatric low-grade glioma: Strata 2, 5, and 6 with long-term outcomes on strata 1, 3, and 4. Neuro-Oncol. 2025;27:2415–28.
Google Scholar
Guo T, Wu C, Zhang J, Yu J, Li G, Jiang H, et al. Dual blockade of EGFR and PI3K signaling pathways offers a therapeutic strategy for glioblastoma. Cell Commun Signal. 2023;21:363.
Google Scholar
Wen, Groot PY, JFd, Battiste J, Goldlust SA, Garner JS, Friend J, et al. Paxalisib in patients with newly diagnosed glioblastoma with unmethylated MGMT promoter status: Final phase 2 study results. J Clin Oncol. 2022;40:2047.
Google Scholar
Robinson GW, Vinitsky A, Bag AK, Chiang J, Li Q, Lin T, et al. LGG-53. Results from the phase 1 and phase 1 expansion cohorts of SJ901: A phase 1/2 trial of single-agent mirdametinib (PD-0325901) in children, adolescents, and young adults with low-grade glioma. Neuro-Oncol. 2024;26:0.
Google Scholar
Berg M, Verhoef JC, Romeijn SG, Merkus FWHM. Uptake of hydrocortisone into the cerebrospinal fluid of rats: comparison of intranasal and intravenous administration in the same animal. Stp Pharma Sci. 2002;12:251–5.
Takahashi N, Miura M, Scott S, Saitoh H, Motegi M, Fujishima N, et al. Dasatinib cerebrospinal fluid concentration and plasma pharmacokinetics: potential for central nervous system prophylaxis in Philadelphia chromosome-positive leukemia. Blood. 2010;116:1807.
Google Scholar
Slayton WB, Schultz KR, Kairalla JA, Devidas M, Mi X, Pulsipher MA, et al. Dasatinib plus intensive chemotherapy in children, adolescents, and young adults with Philadelphia chromosome–positive acute lymphoblastic leukemia: results of children’s oncology group trial AALL0622. J Clin Oncol. 2018;36:2306–14.
Google Scholar
Lester McCully C, Gross A, Cruz Garcia R, Shankarappa P, Odabas A, Rodgers L, et al. EXTH-65. Plasma and cerebrospinal fluid pharmacokinetics comparison of BRAF and MEK inhibitors following single and extended administration in a pre-clinical non-human primate model. Neuro Oncol. 2019;21:vi96.
Google Scholar
Menne T, Slade D, Savage J, Johnson S, Irving J, Kearns P, et al. Selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult acute lymphoblastic leukaemia (SeluDex): study protocol for an international, parallel-group, dose-finding with expansion phase I/II trial. BMJ Open. 2022;12:e059872.
Google Scholar
Minichmayr IK, Knaack U, Gojo J, Senfter D, Haberler C, Azizi AA, et al. Distribution of bevacizumab into the cerebrospinal fluid of children and adolescents with recurrent brain tumors. Paediatr Drugs. 2024;26:429–40.
Google Scholar
Heffron TP, Ndubaku CO, Salphati L, Alicke B, Cheong J, Drobnick J, et al. Discovery of clinical development candidate GDC-0084, a brain penetrant inhibitor of PI3K and mTOR. ACS Med Chem Lett. 2016;7:351–6.
Google Scholar
Hyddmark EMV, Berry DA, Berry NS, Colman H, de Groot JF, Ellingson BM, et al. Update on GBM AGILE: a global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma. J Clin Oncol. 2025;43:TPS2100-TPS.
Google Scholar
