Pediatric T-ALL type-1 and type-2 relapses develop along distinct pathways of clonal evolution.

Child Clonal Evolution / genetics Humans Mutation Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics Recurrence

Journal

Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895

Informations de publication

Date de publication:
07 2022
Historique:
received: 31 01 2022
accepted: 27 04 2022
revised: 18 04 2022
pubmed: 19 5 2022
medline: 8 7 2022
entrez: 18 5 2022
Statut: ppublish

Résumé

The mechanisms underlying T-ALL relapse remain essentially unknown. Multilevel-omics in 38 matched pairs of initial and relapsed T-ALL revealed 18 (47%) type-1 (defined by being derived from the major ancestral clone) and 20 (53%) type-2 relapses (derived from a minor ancestral clone). In both types of relapse, we observed known and novel drivers of multidrug resistance including MDR1 and MVP, NT5C2 and JAK-STAT activators. Patients with type-1 relapses were specifically characterized by IL7R upregulation. In remarkable contrast, type-2 relapses demonstrated (1) enrichment of constitutional cancer predisposition gene mutations, (2) divergent genetic and epigenetic remodeling, and (3) enrichment of somatic hypermutator phenotypes, related to BLM, BUB1B/PMS2 and TP53 mutations. T-ALLs that later progressed to type-2 relapses exhibited a complex subclonal architecture, unexpectedly, already at the time of initial diagnosis. Deconvolution analysis of ATAC-Seq profiles showed that T-ALLs later developing into type-1 relapses resembled a predominant immature thymic T-cell population, whereas T-ALLs developing into type-2 relapses resembled a mixture of normal T-cell precursors. In sum, our analyses revealed fundamentally different mechanisms driving either type-1 or type-2 T-ALL relapse and indicate that differential capacities of disease evolution are already inherent to the molecular setup of the initial leukemia.

Identifiants

DOI: 10.1038/s41375-022-01587-0 PMID: 35585141 PMC: PMC9252914
pubmed: 35585141
doi: 10.1038/s41375-022-01587-0
pii: 10.1038/s41375-022-01587-0
pmc: PMC9252914
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1759-1768

Informations de copyright

© 2022. The Author(s).

Références

Bhojwani D, Pui CH Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol 2013;14. https://doi.org/10.1016/S1470-2045(12)70580-6 .
Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grümayer R, Möricke A, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: Results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118:2077–84.
pubmed: 21719599 doi: 10.1182/blood-2011-03-338707
Kunz JB, Rausch T, Bandapalli OR, Eilers J, Pechanska P, Schuessele S, et al. Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation. Haematologica. 2015;100:1442–50.
pubmed: 26294725 pmcid: 4825305 doi: 10.3324/haematol.2015.129692
Oshima K, Khiabanian H, da Silva-Almeida AC, Tzoneva G, Abate F, Ambesi-Impiombato A, et al. Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2016;113:11306–11.
pubmed: 27655895 pmcid: 5056035 doi: 10.1073/pnas.1608420113
van Vlierberghe P, Ferrando A. The molecular basis of T cell acute lymphoblastic leukemia. J Clin Investig. 2012;122:3398–406.
pubmed: 23023710 pmcid: 3461904 doi: 10.1172/JCI61269
Vicente C, Cools J. The origin of relapse in pediatric T-cell acute lymphoblastic leukemia. Haematologica. 2015;100:1373–5.
pubmed: 26521295 pmcid: 4825310 doi: 10.3324/haematol.2015.136077
Yadav BD, Samuels AL, Wells JE, Sutton R, Venn NC, Bendak K, et al. Heterogeneity in mechanisms of emergent resistance in pediatric T-cell acute lymphoblastic leukemia. Oncotarget. 2016;7:58728–42.
pubmed: 27623214 pmcid: 5312271 doi: 10.18632/oncotarget.11233
Tzoneva G, Perez-Garcia A, Carpenter Z, Khiabanian H, Tosello V, Allegretta M, et al. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nat Med. 2013;19:368–71.
pubmed: 23377281 pmcid: 3594483 doi: 10.1038/nm.3078
Meyer JA, Wang J, Hogan LE, Yang JJ, Dandekar S, Patel JP, et al. Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia. Nat Genet. 2013;45:290–4.
pubmed: 23377183 pmcid: 3681285 doi: 10.1038/ng.2558
Barz MJ, Hof J, Groeneveld-Krentz S, Loh JW, Szymansky A, Astrahantseff K, et al. Subclonal NT5C2 mutations are associated with poor outcomes after relapse of pediatric acute lymphoblastic leukemia. Blood. 2020;135:921–33.
pubmed: 31971569 pmcid: 7218751 doi: 10.1182/blood.2019002499
Hof J, Krentz S, van Schewick C, Körner G, Shalapour S, Rhein P, et al. Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia. J Clin Oncol. 2011;29:3185–93.
pubmed: 21747090 doi: 10.1200/JCO.2011.34.8144
Richter-Pechańska P, Kunz JB, Hof J, Zimmermann M, Rausch T, Bandapalli OR et al. Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia. Blood Cancer Journal 2017; 7. https://doi.org/10.1038/bcj.2017.3 .
Hsiao MH, Yu AL, Yeargin J, Ku D, Haas M. Nonhereditary p53 mutations in T-cell acute lymphoblastic leukemia are associated with the relapse phase. Blood. 1994;83:2922–30.
pubmed: 8180387 doi: 10.1182/blood.V83.10.2922.2922
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.
pubmed: 25253770 pmcid: 4246039 doi: 10.1182/blood-2014-04-531871
Gianfelici V, Chiaretti S, Demeyer S, di Giacomo F, Messina M, la Starza R, et al. RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications. Haematologica. 2016;101:941–50.
pubmed: 27151993 pmcid: 4967573 doi: 10.3324/haematol.2015.139410
Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306. www.sciencemag.org (Accessed 22 Mar2022).
Single-cell DNA amplicon sequencing reveals clonal heterogeneity and evolution in T-cell acute lymphoblastic leukemia. Mission Bio. https://missionbio.com/resources/publications/alberti-servera-blood-2021/ (Accessed 22 Mar2022).
Kox C, Zimmermann M, Stanulla M, Leible S, Schrappe M, Ludwig WD, et al. The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL–BFM 2000 protocol can be separated from FBXW7 loss of function. Leukemia. 2010;24:2005.
pubmed: 20944675 pmcid: 3035973 doi: 10.1038/leu.2010.203
Richter‐Pechańska P, Kunz JB, Bornhauser B, Knebel Doeberitz C, Rausch T, Erarslan‐Uysal B, et al. PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia. EMBO Molecular Medicine 2018; 10. https://doi.org/10.15252/emmm.201809443 .
Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N. Engl J Med. 2015;373:2336–46.
pubmed: 26580448 pmcid: 4734119 doi: 10.1056/NEJMoa1508054
Stieglitz E, Loh ML. Genetic predispositions to childhood leukemia. Therapeutic Adv Hematol. 2013;4:270–90.
doi: 10.1177/2040620713498161
Topka S, Vijai J, Walsh MF, Jacobs L, Maria A, Villano D, et al. Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. PLoS Genetics 2015; 11. https://doi.org/10.1371/journal.pgen.1005262 .
Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet. 2017;49:1211–8.
pubmed: 28671688 pmcid: 5535770 doi: 10.1038/ng.3909
Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505:302–8.
pubmed: 24429628 pmcid: 4975511 doi: 10.1038/nature12981
Assenov Y, Müller F, Lutsik P, Walter J, Lengauer T, Bock C. Comprehensive analysis of DNA methylation data with RnBeads. Nat Methods. 2014;11:1138–40.
pubmed: 25262207 pmcid: 4216143 doi: 10.1038/nmeth.3115
R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria 2019. https://www.R-project.org/ .
Wong M, Mayoh C, Lau LMS, Khuong-Quang DA, Pinese M, Kumar A, et al. Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer. Nat Med. 2020;26:1742–53.
pubmed: 33020650 doi: 10.1038/s41591-020-1072-4
Newman S, Nakitandwe J, Kesserwan CA, Azzato EM, Wheeler DA, Rusch M, et al. Genomes for kids: the scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Disco. 2021;11:3008–35.
doi: 10.1158/2159-8290.CD-20-1631
Gröbner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, et al. The landscape of genomic alterations across childhood cancers. Nature. 2018;555:321–7.
pubmed: 29489754 doi: 10.1038/nature25480
Rodriguez-Martin B, Alvarez EG, Baez-Ortega A, Zamora J, Supek F, Demeulemeester J, et al. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nat Genet. 2020;52:306–19.
pubmed: 32024998 pmcid: 7058536 doi: 10.1038/s41588-019-0562-0
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43.
pubmed: 32461654 pmcid: 7334197 doi: 10.1038/s41586-020-2308-7
Wang K, Sanchez-Martin M, Wang X, Knapp KM, Koche R, Vu L, et al. Patient-derived xenotransplants can recapitulate the genetic driver landscape of acute leukemias. Leukemia. 2017;31:151–8.
pubmed: 27363283 doi: 10.1038/leu.2016.166
Borssén M, Palmqvist L, Karrman K, Abrahamsson J, Behrendtz M, Heldrup J, et al. Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia. PLOS ONE. 2013;8:e65373.
pubmed: 23762353 pmcid: 3675104 doi: 10.1371/journal.pone.0065373
Erarslan‐Uysal B, Kunz JB, Rausch T, Richter‐Pechańska P, Belzen IA, Frismantas V et al. Chromatin accessibility landscape of pediatric T‐lymphoblastic leukemia and human T‐cell precursors. EMBO Molecular Medicine 2020; 12. https://doi.org/10.15252/emmm.202012104 .
Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.
pubmed: 25822800 pmcid: 4739640 doi: 10.1038/nmeth.3337
Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5:219–34.
pubmed: 16518375 doi: 10.1038/nrd1984
Xiao YS, Zeng D, Liang YK, Wu Y, Li MF, Qi YZ, et al. Major vault protein is a direct target of Notch1 signaling and contributes to chemoresistance in triple-negative breast cancer cells. Cancer Lett. 2019;440-1:156–67.
doi: 10.1016/j.canlet.2018.09.031
Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE, Bäsecke J, et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia. 2008;22:686–707.
pubmed: 18337767 doi: 10.1038/leu.2008.26
Vainchenker W, Constantinescu SN. JAK/STAT signaling in hematological malignancies. Oncogene. 2012;32:2601–13.
pubmed: 22869151 doi: 10.1038/onc.2012.347
Migone TS, Lin JX, Cereseto A, Mulloy JC, O’Shea JJ, Franchini G, et al. Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science. 1995;269:79–81.
pubmed: 7604283 doi: 10.1126/science.7604283
Mullighan CG. Molecular genetics of B-precursor acute lymphoblastic leukemia. J Clin Investig. 2012;122:3407–15.
pubmed: 23023711 pmcid: 3461902 doi: 10.1172/JCI61203
Raetz EA, Teachey DT. T-cell acute lymphoblastic leukemia. Hematol: Am Soc Hematol Educ Program. 2016;2016:580.
doi: 10.1182/asheducation-2016.1.580
Steiner E, Holzmann K, Pirker C, Elbling L, Micksche M, Sutterlüty H, et al. The major vault protein is responsive to and interferes with interferon-γ-mediated STAT1 signals. J Cell Sci. 2006;119:459–69.
pubmed: 16418217 doi: 10.1242/jcs.02773
Mossink MH, van Zon A, Scheper RJ, Sonneveld P, Wiemer EAC. Vaults: a ribonucleoprotein particle involved in drug resistance? Oncogene. 2003;22:7458–67.
pubmed: 14576851 doi: 10.1038/sj.onc.1206947
Vitali C, Bassani C, Chiodoni C, Fellini E, Guarnotta C, Miotti S, et al. SOCS2 controls proliferation and stemness of hematopoietic cells under stress conditions and its deregulation marks unfavorable acute leukemias. Cancer Res. 2015;75:2387–99.
pubmed: 25858143 doi: 10.1158/0008-5472.CAN-14-3625
Shochat C, Tal N, Bandapalli OR, Palmi C, Ganmore I, te Kronnie G, et al. Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias. J Exp Med. 2011;208:901–8.
pubmed: 21536738 pmcid: 3092356 doi: 10.1084/jem.20110580
Shochat C, Tal N, Gryshkova V, Birger Y, Bandapalli OR, Cazzaniga G, et al. Novel activating mutations lacking cysteine in type i cytokine receptors in acute lymphoblastic leukemia. Blood. 2014;124:106–10.
pubmed: 24787007 doi: 10.1182/blood-2013-10-529685
Zenatti PP, Ribeiro D, Li W, Zuurbier L, Silva MC, Paganin M, et al. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet. 2011;43:932–41.
pubmed: 21892159 pmcid: 7424552 doi: 10.1038/ng.924
Li Y, Buijs-Gladdines JGCAM, Canté-Barrett K, Stubbs AP, Vroegindeweij EM, Smits WK, et al. IL-7 Receptor mutations and steroid resistance in pediatric t cell acute lymphoblastic leukemia: a genome sequencing study. PLoS Medicine 2016; 13. https://doi.org/10.1371/journal.pmed.1002200 .
Vicente C, Schwab C, Broux M, Geerdens E, Degryse S, Demeyer S, et al. Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia. Haematologica. 2015;100:1301–10.
pubmed: 26206799 pmcid: 4591762 doi: 10.3324/haematol.2015.130179
Alsadeq A, Lenk L, Vadakumchery A, Cousins A, Vokuhl C, Khadour A, et al. IL7R is associated with CNS infiltration and relapse in pediatric B-cell precursor acute lymphoblastic leukemia. Blood. 2018;132:1614–7.
pubmed: 30154115 pmcid: 6238156 doi: 10.1182/blood-2018-04-844209
Gianfelici V, Messina M, Paoloni F, Peragine N, Lauretti A, Fedullo AL, et al. IL7R overexpression in adult acute lymphoblastic leukemia is associated to JAK/STAT pathway mutations and identifies patients who could benefit from targeted therapies. Leuk Lymphoma. 2019;60:829–32.
pubmed: 30188230 doi: 10.1080/10428194.2018.1499906
van Tilburg CM, Pfaff E, Pajtler KW, Langenberg KPS, Fiesel P, Jones BC, et al. The pediatric precision oncology inform registry: clinical outcome and benefit for patients with very high-evidence targets. Cancer Disco. 2021;11:2764–79.
doi: 10.1158/2159-8290.CD-21-0094

Auteurs

Paulina Richter-Pechańska (P)

Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.
Hopp Children´s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Molecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of the University of Heidelberg, Heidelberg, Germany.

Joachim B Kunz (JB)

Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.
Hopp Children´s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Molecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of the University of Heidelberg, Heidelberg, Germany.

Tobias Rausch (T)

Molecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of the University of Heidelberg, Heidelberg, Germany.
European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
ORCID: 0000-0001-5773-5620

Büşra Erarslan-Uysal (B)

Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.
Hopp Children´s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Molecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of the University of Heidelberg, Heidelberg, Germany.

Beat Bornhauser (B)

Division of Pediatric Oncology, University Children's Hospital, Zürich, Switzerland.
ORCID: 0000-0003-2890-3191

Viktoras Frismantas (V)

Division of Pediatric Oncology, University Children's Hospital, Zürich, Switzerland.

Yassen Assenov (Y)

Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Martin Zimmermann (M)

Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.

Margit Happich (M)

Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.
Hopp Children´s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.

Caroline von Knebel-Doeberitz (C)

Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.
Hopp Children´s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Molecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of the University of Heidelberg, Heidelberg, Germany.

Nils von Neuhoff (N)

Department of Pediatrics III, University Hospital, University of Duisburg-Essen, Essen, Germany.

Rolf Köhler (R)

Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.

Martin Stanulla (M)

Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
ORCID: 0000-0002-3834-0727

Martin Schrappe (M)

Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Gunnar Cario (G)

Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Gabriele Escherich (G)

Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Renate Kirschner-Schwabe (R)

Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.
German Cancer Consortium (DKTK), and German Cancer Research Center (DKFZ), Heidelberg, Germany.
ORCID: 0000-0001-6335-3274

Cornelia Eckert (C)

Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.
German Cancer Consortium (DKTK), and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Smadar Avigad (S)

Molecular Oncology, Felsenstein Medical Research Center and Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.

Stefan M Pfister (SM)

Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.
Hopp Children´s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Martina U Muckenthaler (MU)

Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.
Hopp Children´s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Molecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of the University of Heidelberg, Heidelberg, Germany.
ORCID: 0000-0002-3778-510X

Jean-Pierre Bourquin (JP)

Division of Pediatric Oncology, University Children's Hospital, Zürich, Switzerland.

Jan O Korbel (JO)

Molecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of the University of Heidelberg, Heidelberg, Germany. korbel@embl.de.
European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. korbel@embl.de.
ORCID: 0000-0002-2798-3794

Andreas E Kulozik (AE)

Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.
Hopp Children´s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.
Molecular Medicine Partnership Unit (MMPU), EMBL and Medical Faculty of the University of Heidelberg, Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.
ORCID: 0000-0003-1953-0848

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Pediatric T-ALL type-1 and type-2 relapses...
questionsmedicales.fr › Phénomènes génétiques › Évolution clonale › Pediatric T-ALL type-1 and type-2 relapses...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Pediatric T-ALL type-1 and type-2 relapses...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Pediatric T-ALL type-1 and type-2 relapses...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Leucémie lymphoïde › Leucémie-lymphome lymphoblastique à précurseurs B et T › Leucémie-lymphome lymphoblastique à précurseurs T › Pediatric T-ALL type-1 and type-2 relapses...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Récidive › Pediatric T-ALL type-1 and type-2 relapses...