The Gene Expression Classifier ALLCatchR Identifies B-cell Precursor ALL Subtypes and Underlying Developmental Trajectories Across Age

被引：24

作者：

Beder, Thomas ^{[1
]}

Hansen, Bjoern-Thore ^{[1
]}

Hartmann, Alina M. ^{[1
,2
]}

Zimmermann, Johannes ^{[3
]}

Amelunxen, Eric ^{[1
]}

Wolgast, Nadine ^{[1
,2
]}

Walter, Wencke ^{[4
]}

Zaliova, Marketa ^{[5
,6
]}

Antic, Zeljko ^{[7
]}

Chouvarine, Philippe ^{[7
]}

Bartsch, Lorenz ^{[1
]}

Barz, Malwine J. ^{[1
,2
]}

Bultmann, Miriam ^{[1
]}

Horns, Johanna ^{[1
]}

Bendig, Sonja ^{[1
,2
]}

Kaessens, Jan ^{[1
]}

Kaleta, Christoph ^{[3
]}

Cario, Gunnar ^{[2
,8
]}

Schrappe, Martin ^{[2
,8
]}

Neumann, Martin ^{[1
,2
]}

Goekbuget, Nicola ^{[9
]}

Bergmann, Anke Katharina ^{[7
]}

Trka, Jan ^{[5
,6
]}

Haferlach, Claudia ^{[4
]}

Brueggemann, Monika ^{[1
,2
]}

Baldus, Claudia D. ^{[1
,2
]}

Bastian, Lorenz ^{[1
,2
]}

机构：

[1] Univ Hosp Schleswig Holstein, Med Dept 2, Kiel, Germany

[2] Deutsch Forsch gemeinschaft, Clin Res Unit CATCH ALL KFO 5010 1, Bonn, Germany

[3] Christian Albrechts Univ Kiel, Inst Expt Med, Res Grp Med Syst Biol, Kiel, Germany

[4] MLL Munich Leukemia Lab, Munich, Germany

[5] Charles Univ Prague, Fac Med 2, Childhood Leukaemia Invest Prague, Prague, Czech Republic

[6] Univ Hosp Motol, Prague, Czech Republic

[7] Hannover Med Sch MHH, Dept Human Genet, Hannover, Germany

[8] Univ Hosp Schleswig Holstein, Dept Pediat, Kiel, Germany

[9] Goethe Univ Hosp, Dept Med 2, Hematol Oncol, Frankfurt, Germany

来源：

HEMASPHERE | 2023年 / 7卷 / 09期

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; SELECTION; DEFINE; MODELS;

D O I：

10.1097/HS9.0000000000000939

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Current classifications (World Health Organization-HAEM5/ICC) define up to 26 molecular B-cell precursor acute lymphoblastic leukemia (BCP-ALL) disease subtypes by genomic driver aberrations and corresponding gene expression signatures. Identification of driver aberrations by transcriptome sequencing (RNA-Seq) is well established, while systematic approaches for gene expression analysis are less advanced. Therefore, we developed ALLCatchR, a machine learning-based classifier using RNA-Seq gene expression data to allocate BCP-ALL samples to all 21 gene expression-defined molecular subtypes. Trained on n = 1869 transcriptome profiles with established subtype definitions (4 cohorts; 55% pediatric / 45% adult), ALLCatchR allowed subtype allocation in 3 independent hold-out cohorts (n = 1018; 75% pediatric / 25% adult) with 95.7% accuracy (averaged sensitivity across subtypes: 91.1% / specificity: 99.8%). High-confidence predictions were achieved in 83.7% of samples with 98.9% accuracy. Only 1.2% of samples remained unclassified. ALLCatchR outperformed existing tools and identified novel driver candidates in previously unassigned samples. Additional modules provided predictions of samples blast counts, patient's sex, and immunophenotype, allowing the imputation in cases where these information are missing. We established a novel RNA-Seq reference of human B-lymphopoiesis using 7 FACS-sorted progenitor stages from healthy bone marrow donors. Implementation in ALLCatchR enabled projection of BCP-ALL samples to this trajectory. This identified shared proximity patterns of BCP-ALL subtypes to normal lymphopoiesis stages, extending immunophenotypic classifications with a novel framework for developmental comparisons of BCP-ALL. ALLCatchR enables RNA-Seq routine application for BCP-ALL diagnostics with systematic gene expression analysis for accurate subtype allocation and novel insights into underlying developmental trajectories.

引用

页数：13

共 41 条

[1] Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) [J].

Akasaka, Takashi ;

Balasas, Theodore ;

Russell, Lisa J. ;

Sugimoto, Kei-ji ;

Majid, Aneela ;

Walewska, Renata ;

Karran, E. Loraine ;

Brown, David G. ;

Cain, Kelvin ;

Harder, Lana ;

Gesk, Stefan ;

Martin-Subero, Jose Ignacio ;

Atherton, Mark G. ;

Brueggemann, Monika ;

Calasanz, Maria Jose ;

Davies, Teresa ;

Haas, Oskar A. ;

Hagemeijer, Anne ;

Kempski, Helena ;

Lessard, Michel ;

Lillington, Debra M. ;

Moore, Sarah ;

Nguyen-Khac, Florence ;

Radford-Weiss, Isabelle ;

Schoch, Claudia ;

Struski, Stephanie ;

Talley, Polly ;

Welham, Melanie J. ;

Worley, Helen ;

Strefford, Jon C. ;

Harrison, Christine J. ;

Siebert, Reiner ;

Dyer, Martin J. S. .

BLOOD, 2007, 109 (08) :3451-3461

[2] The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms [J].

Alaggio, Rita ;

Amador, Catalina ;

Anagnostopoulos, Ioannis ;

Attygalle, Ayoma D. ;

Araujo, Iguaracyra Barreto de Oliveira ;

Berti, Emilio ;

Bhagat, Govind ;

Borges, Anita Maria ;

Boyer, Daniel ;

Calaminici, Mariarita ;

Chadburn, Amy ;

Chan, John K. C. ;

Cheuk, Wah ;

Chng, Wee-Joo ;

Choi, John K. ;

Chuang, Shih-Sung ;

Coupland, Sarah E. ;

Czader, Magdalena ;

Dave, Sandeep S. ;

de Jong, Daphne ;

Du, Ming-Qing ;

Elenitoba-Johnson, Kojo S. ;

Ferry, Judith ;

Geyer, Julia ;

Gratzinger, Dita ;

Guitart, Joan ;

Gujral, Sumeet ;

Harris, Marian ;

Harrison, Christine J. ;

Hartmann, Sylvia ;

Hochhaus, Andreas ;

Jansen, Patty M. ;

Karube, Kennosuke ;

Kempf, Werner ;

Khoury, Joseph ;

Kimura, Hiroshi ;

Klapper, Wolfram ;

Kovach, Alexandra E. ;

Kumar, Shaji ;

Lazar, Alexander J. ;

Lazzi, Stefano ;

Leoncini, Lorenzo ;

Leung, Nelson ;

Leventaki, Vasiliki ;

Li, Xiao-Qiu ;

Lim, Megan S. ;

Liu, Wei-Ping ;

Louissaint, Abner, Jr. ;

Marcogliese, Andrea ;

Medeiros, L. Jeffrey .

LEUKEMIA, 2022, 36 (07) :1720-1748

[3] International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data [J].

Arber, Daniel A. ;

Orazi, Attilio ;

Hasserjian, Robert P. ;

Borowitz, Michael J. ;

Calvo, Katherine R. ;

Kvasnicka, Hans-Michael ;

Wang, Sa A. ;

Bagg, Adam ;

Barbui, Tiziano ;

Branford, Susan ;

Bueso-Ramos, Carlos E. ;

Cortes, Jorge E. ;

Dal Cin, Paola ;

DiNardo, Courtney D. ;

Dombret, Herve ;

Duncavage, Eric J. ;

Ebert, Benjamin L. ;

Estey, Elihu H. ;

Facchetti, Fabio ;

Foucar, Kathryn ;

Gangat, Naseema ;

Gianelli, Umberto ;

Godley, Lucy A. ;

Gokbuget, Nicola ;

Gotlib, Jason ;

Hellstrom-Lindberg, Eva ;

Hobbs, Gabriela S. ;

Hoffman, Ronald ;

Jabbour, Elias J. ;

Kiladjian, Jean-Jacques ;

Larson, Richard A. ;

Le Beau, Michelle M. ;

Loh, Mignon L. -C. ;

Lowenberg, Bob ;

Macintyre, Elizabeth ;

Malcovati, Luca ;

Mullighan, Charles G. ;

Niemeyer, Charlotte ;

Odenike, Olatoyosi M. ;

Ogawa, Seishi ;

Orfao, Alberto ;

Papaemmanuil, Elli ;

Passamonti, Francesco ;

Porkka, Kimmo ;

Pui, Ching-Hon ;

Radich, Jerald P. ;

Reiter, Andreas ;

Rozman, Maria ;

Rudelius, Martina ;

Savona, Michael R. .

BLOOD, 2022, 140 (11) :1200-1228

[4] RNAseqCNV: analysis of large-scale copy number variations from RNA-seq data [J].

Barinka, Jan ;

Hu, Zunsong ;

Wang, Lu ;

Wheeler, David A. ;

Rahbarinia, Delaram ;

McLeod, Clay ;

Gu, Zhaohui ;

Mullighan, Charles G. .

LEUKEMIA, 2022, 36 (06) :1492-1498

[5] UBTF::ATXN7L3 gene fusion defines novel B cell precursor ALL subtype with CDX2 expression and need for intensified treatment [J].

Bastian, Lorenz ;

Hartmann, Alina M. ;

Beder, Thomas ;

Haenzelmann, Sonja ;

Kaessens, Jan ;

Bultmann, Miriam ;

Hoeppner, Marc P. ;

Franzenburg, Soeren ;

Wittig, Michael ;

Franke, Andre ;

Nagel, Inga ;

Spielmann, Malte ;

Reimer, Niklas ;

Busch, Hauke ;

Schwartz, Stefan ;

Steffen, Bjoern ;

Viardot, Andreas ;

Doehner, Konstanze ;

Kondakci, Mustafa ;

Wulf, Gerald ;

Wendelin, Knut ;

Renzelmann, Andrea ;

Kiani, Alexander ;

Trautmann, Heiko ;

Neumann, Martin ;

Goekbuget, Nicola ;

Brueggemann, Monika ;

Baldus, Claudia D. .

LEUKEMIA, 2022, 36 (06) :1676-1680

[6] PAX5 biallelic genomic alterations define a novel subgroup of B-cell precursor acute lymphoblastic leukemia [J].

Bastian, Lorenz ;

Schroeder, Michael P. ;

Eckert, Cornelia ;

Schlee, Cornelia ;

Tanchez, Jutta Ortiz ;

Kaempf, Sebastian ;

Wagner, Dimitrios L. ;

Schulze, Veronika ;

Isaakidis, Konstandina ;

Lazaro-Navarro, Juan ;

Haenzelmann, Sonja ;

James, Alva Rani ;

Ekici, Arif ;

Burmeister, Thomas ;

Schwartz, Stefan ;

Schrappe, Martin ;

Horstmann, Martin ;

Vosberg, Sebastian ;

Krebs, Stefan ;

Blum, Helmut ;

Hecht, Jochen ;

Greif, Philipp A. ;

Rieger, Michael A. ;

Brueggemann, Monika ;

Goekbuget, Nicola ;

Neumann, Martin ;

Baldus, Claudia D. .

LEUKEMIA, 2019, 33 (08) :1895-1909

[7]

BENE MC, 1995, LEUKEMIA, V9, P1783

[8] BCR-ABL1-like cases in pediatric acute lymphoblastic leukemia: a comparison between DCOG/Erasmus MC and COG/St. Jude signatures [J].

Boer, Judith M. ;

Marchante, Joao R. M. ;

Evans, William E. ;

Horstmann, Martin A. ;

Escherich, Gabriele ;

Pieters, Rob ;

Den Boer, Monique L. .

HAEMATOLOGICA, 2015, 100 (09) :E354-E357

[9] Single-cell multiomics reveals increased plasticity, resistant populations, and stem-cell-like blasts in KMT2A-rearranged leukemia [J].

Chen, Changya ;

Yu, Wenbao ;

Alikarami, Fatemeh ;

Qiu, Qi ;

Chen, Chia-Hui ;

Flournoy, Jennifer ;

Gao, Peng ;

Uzun, Yasin ;

Fang, Li ;

Davenport, James W. ;

Hu, Yuxuan ;

Zhu, Qin ;

Wang, Kai ;

Libbrecht, Clara ;

Felmeister, Alex ;

Rozich, Isaiah ;

Ding, Yang-Yang ;

Hunger, Stephen P. ;

Felix, Carolyn A. ;

Wu, Hao ;

Brown, Patrick A. ;

Guest, Erin M. ;

Barrett, David M. ;

Bernt, Kathrin M. ;

Tan, Kai .

BLOOD, 2022, 139 (14) :2198-2211

[10] Transcriptional and Mutational Profiling of B-Other Acute Lymphoblastic Leukemia for Improved Diagnostics [J].

Chouvarine, Philippe ;

Antic, Zeljko ;

Lentes, Jana ;

Schroder, Charlotte ;

Alten, Julia ;

Brueggemann, Monika ;

Pau, Enrique Carrillo-de Santa ;

Illig, Thomas ;

Laguna, Teresa ;

Schewe, Denis ;

Stanulla, Martin ;

Tang, Ming ;

Zimmermann, Martin ;

Schrappe, Martin ;

Schlegelberger, Brigitte ;

Cario, Gunnar ;

Bergmann, Anke K. .

CANCERS, 2021, 13 (22)

← 1 2 3 4 5 →