TY - JOUR
T1 - IKZF1 gene deletions drive resistance to cytarabine in B-cell precursor acute lymphoblastic leukemia
AU - Vervoort, Britt M T
AU - Butler, Miriam
AU - Grünewald, Kari J T
AU - Schenau, Dorette S van Ingen
AU - Tee, Trisha M
AU - Lucas, Luc
AU - Huitema, Alwin D R
AU - Boer, Judith M
AU - Bornhauser, Beat C
AU - Bourquin, Jean-Pierre
AU - Hoogerbrugge, Peter M
AU - Van der Velden, Vincent H J
AU - Kuiper, Roland P
AU - Van der Meer, Laurens T
AU - Van Leeuwen, Frank N
PY - 2024/12/1
Y1 - 2024/12/1
N2 - 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 AraC, a key component of both upfront and relapsed treatment protocols. We attribute this resistance, in part, to diminished import and incorporation of cytarabine (AraC) due to reduced expression of the solute carrier hENT1. Moreover, we find 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 patient group could benefit from alternative antimetabolites, or targeted therapies that resensitize the cells to AraC.
AB - 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 AraC, a key component of both upfront and relapsed treatment protocols. We attribute this resistance, in part, to diminished import and incorporation of cytarabine (AraC) due to reduced expression of the solute carrier hENT1. Moreover, we find 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 patient group could benefit from alternative antimetabolites, or targeted therapies that resensitize the cells to AraC.
KW - Animals
KW - Antimetabolites, Antineoplastic/therapeutic use
KW - Cell Line, Tumor
KW - Cyclin-Dependent Kinases/genetics
KW - Cytarabine/pharmacology
KW - Drug Resistance, Neoplasm/genetics
KW - Gene Deletion
KW - Gene Expression Regulation, Leukemic/drug effects
KW - Humans
KW - Ikaros Transcription Factor/genetics
KW - MDS1 and EVI1 Complex Locus Protein/genetics
KW - Mice
KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics
UR - https://www.mendeley.com/catalogue/7231ff48-6e7f-3546-854b-011a1a07969b/
U2 - 10.3324/haematol.2023.284357
DO - 10.3324/haematol.2023.284357
M3 - Article
C2 - 38841778
SN - 0390-6078
VL - 109
SP - 3904
EP - 3917
JO - Haematologica
JF - Haematologica
IS - 12
ER -