IKZF1 gene deletions drive resistance to cytarabine in B-cell precursor acute lymphoblastic leukemia.
| Title: | IKZF1 gene deletions drive resistance to cytarabine in B-cell precursor acute lymphoblastic leukemia. |
|---|---|
| Authors: | Vervoort BMT; Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS.; Butler M; Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS.; Grünewald KJT; Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS.; Schenau DSVI; Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS.; Tee TM; Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS.; Lucas L; Netherlands Cancer Institute, Amsterdam.; Huitema ADR; Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS, the Netherlands; Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht.; Boer JM; Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS.; Bornhauser BC; Department of Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, CH-8008.; Bourquin JP; Department of Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, CH-8008.; Hoogerbrugge PM; Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS.; Van der Velden VHJ; Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam.; Kuiper RP; Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS, the Netherlands; Department of Genetics, Utrecht University Medical Center, Utrecht University, Utrecht The Netherlands.; Van der Meer LT; Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS.; Van Leeuwen FN; Princess Máxima Center for Pediatric Oncology, Utrecht, 3584 CS. F.N.vanleeuwen@prinsesmaximacentrum.nl. |
| Source: | Haematologica [Haematologica] 2024 Dec 01; Vol. 109 (12), pp. 3904-3917. Date of Electronic Publication: 2024 Dec 01. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Ferrata Storti Foundation Country of Publication: Italy NLM ID: 0417435 Publication Model: Electronic Cited Medium: Internet ISSN: 1592-8721 (Electronic) Linking ISSN: 03906078 NLM ISO Abbreviation: Haematologica Subsets: MEDLINE |
| Imprint Name(s): | Publication: 1999- : Pavia, Italy : Ferrata Storti Foundation; Original Publication: Pavia [etc.] |
| MeSH Terms: | Ikaros Transcription Factor*/genetics ; Cytarabine*/pharmacology ; Cytarabine*/therapeutic use ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma*/genetics ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma*/drug therapy ; Drug Resistance, Neoplasm*/genetics ; Gene Deletion*; MDS1 and EVI1 Complex Locus Protein/genetics ; Antimetabolites, Antineoplastic/therapeutic use ; Antimetabolites, Antineoplastic/pharmacology ; Cyclin-Dependent Kinases/genetics ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Gene Expression Regulation, Leukemic/drug effects ; Humans ; Animals ; Mice ; Cell Line, Tumor |
| Abstract: | IKZF1 deletions occur in 10-15% of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and predict a poor outcome. However, the impact of IKZF1 loss on sensitivity to drugs used in contemporary treatment protocols has remained underexplored. Here we show in experimental models and in patients that loss of IKZF1 promotes resistance to cytarabine (AraC), a key component of both upfront and relapsed treatment protocols. We attribute this resistance, in part, to diminished import and incorporation of AraC due to reduced expression of the solute carrier hENT1. Moreover, we found elevated mRNA expression of Evi1, a known driver of therapy resistance in myeloid malignancies. Finally, a kinase directed CRISPR/Cas9-screen identified that inhibition of either mediator kinases CDK8/19 or casein kinase 2 can restore response to AraC. We conclude that this high-risk group of patients could benefit from alternative antimetabolites, or targeted therapies that re-sensitize leukemic cells to AraC. |
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| Substance Nomenclature: | 148971-36-2 (Ikaros Transcription Factor); 0 (IKZF1 protein, human); 04079A1RDZ (Cytarabine); 0 (MDS1 and EVI1 Complex Locus Protein); 0 (MECOM protein, human); EC 2.7.11.22 (CDK19 protein, human); 0 (Antimetabolites, Antineoplastic); EC 2.7.11.22 (Cyclin-Dependent Kinases) |
| Entry Date(s): | Date Created: 20240606 Date Completed: 20241202 Latest Revision: 20241204 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11609812 |
| DOI: | 10.3324/haematol.2023.284357 |
| PMID: | 38841778 |
| Database: | MEDLINE |
Journal Article