Page 281 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Previously, interference with pre-BCR signaling has been suggested as a therapeutic option for TCF3-rearranged ALL12 and the inhibitors ibrutinib, dasatinib and idelalisib to be effective against TCF3::PBX1+ B-ALL.5,12,13 Inhibition of BTK, a downstream signaling kinase of the BCR, by ibrutinib is clinically beneficial in BCR+ B-cell malignancies such as non-Hodgkin lymphomas and multiple myeloma. However, in our analyses, the response of TCF3::PBX1+ B-ALL cell lines to BTK-targeting drugs was low and not corresponding to pre-BCR expression. This is in line with the observation that ibrutinib exerts a cytostatic rather than a cytotoxic effect on pre-BCR+ B-ALL cells5 and is further supported by the lack of in vivo effectivity against TCF3::PBX1+ primogafts.14 However, TCF3::PBX1+ PDX samples responded well to the tyrosine kinase inhibitor dasatinib.2 Still, high doses might be required for targets other than BCR::ABL1 and might be limited in the relapse setting due to toxicity.13
Taken together, proteomic-based profiling is a powerful tool to discover highly specific and sensitive cancer biomarkers and oncogenic pathway activation.15 Here, we uncovered pro- teomic alterations associated with TCF3::HLF+ or TCF3::PBX1+ B-ALL and revealed potential therapeutic options for these subtypes. These include previously known sensitivities for TCF3::HLF+ (e.g., BCL2 and mTOR) and TCF3::PBX1+ B-ALL (e.g., aurora kinase and polo-like kinase), as well as potential novel drug targets, such as MDM2 and DNA/RNA synthesis for TCF3::HLF+ or microtubule/tubulin and CDK for TCF3::P- BX1+ leukemic cells. Our data suggest that TCF3::PBX1+ B-ALL might be sensitive to treatment with selective BLK inhibitors, especially in combination with microtubule/tubulin targeting drugs, such as ixabepilone. Due to high BLK expression in TCF3::PBX1+ B-ALL cells, such inhibitors could selectively eradicate leukemic cells at doses eliciting less side-effects on normal tissue. A limitation of our study is that this was not tested in mouse models. In future studies, it would be interesting to apply BLK inhibition to suitable mouse models of TCF3::PBX1+ leukemia and to test synergism with other drugs. Larger numbers of patient samples need to be tested to show the applicability for TCF3::PBX1+ leukemia.
Authors
Lena Blümel,1,2 Flavia Bernardi,3,4 Daniel Picard,1,2 Jacob Torrejon Diaz,3,4 Vera H. Jepsen,1,5 Rebecca Hasselmann,1,5 Julian Schliehe- Diecks,1,5 Jasmin Bartl,1,2,6 Nan Qin,1,2 Beat Bornhauser,7 Sanil Bhatia,1,5 Blerim Marovka,7 Veronique Marsaud,3,4 Florent Dingli,8 Damarys Loew,8 Martin Stanulla,9# Jean-Pierre Bourqin,7# Arndt Borkhardt,1,5# Marc Remke,1,2# Olivier Ayrault3,4# and Ute Fischer1,5#
1Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany; 2Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), partner site Essen/
Düsseldorf, Düsseldorf, Germany; 3Institut Curie, CNRS UMR, INSERM, PSL Research University, Orsay, France; 4CNRS UMR 3347, INSERM U1021, Université Paris Sud, Université Paris-Saclay, Orsay, France; 5German Cancer Consortium (DKTK), partner site Essen/ Düsseldorf, Düsseldorf, Germany; 6Group for Interdisciplinary Neurobiology and Immunology - INI-research, Institute of Zoology, University of Hamburg, Hamburg, Germany; 7Department of Oncology and Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland; 8Institut Curie, PSL Research University, Centre de Recherche, CurieCoreTech Spectrométrie de Masse Protéomique, Paris, France and 9Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
#MS, J-PB, AB, MR, OA and UF contributed equally as senior authors.
Correspondence:
U. FISCHER - ute.fischer@med.uni-duesseldorf.de
https://doi.org/10.3324/haematol.2023.283928
Received: July 17, 2023. Accepted: February 15, 2024. Early view: February 29, 2024.
©2024 Ferrata Storti Foundation Published under a CC BY-NC license
Disclosures
No conflicts of interest to disclose.
Contributions
LB, JB, MS, J-PB, AB, MR, OA and UF planned and directed the study. Patient-derived xenograft models were provided by BB, BM and J-PB. FB, JTD, VM, FD, DL and OA conducted proteomic profiling and analyzed proteomic data. DP provided bioinformatic analyses. LB designed and performed the in vitro experiments, supported by VJ, JS-D and RH. NQ generated dose-response curves. SB provided intellectual contributions to the project and to the interpretation of the results. LB, VJ and UF wrote the manuscript. Figures were designed and drafted by LB, DP, NQ, VJ, JS-D and UF. All authors edited and contributed to the final manuscript.
Acknowledgments
Frauke-Dorothee Meyer, Sarah Göbbels and Bianca Killing are acknowledged for excellent technical assistance.
Funding
This work was supported by grants from the German José-Carreras Leukemia Foundation (DJCLS 07 R/2019 [to AB], DJCLS 18R/2021 [to UF], DJCLS 21R/2019 [to MR and UF]), the Elterninitiative Kinderkrebsklinik e.V. (to MR and JB), the Katharina-Hardt-Stiftung (to AB), the parents’ initiative Löwenstern e.V. (to AB and UF), the Gert-und-Susanna-Meyer Foundation (to MR), the Research Commission of the Medical Faculty of the Heinrich Heine University (to MR and NQ), the German Research Foundation (HE 8807/3-1 [to
Haematologica | 109 July 2024
2295