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 - van Ingen Schenau, Dorette S.
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.
N1 - Publisher Copyright:
©2024 Ferrata Storti Foundation.
PY - 2024/12
Y1 - 2024/12
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 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=85210963517&partnerID=8YFLogxK
U2 - 10.3324/haematol.2023.284357
DO - 10.3324/haematol.2023.284357
M3 - Article
C2 - 38841778
AN - SCOPUS:85210963517
SN - 0390-6078
VL - 109
SP - 3904
EP - 3905
JO - Haematologica
JF - Haematologica
IS - 12
ER -