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1.
Haematologica ; 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38841778

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 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.

2.
Blood ; 138(23): 2383-2395, 2021 12 09.
Article in English | MEDLINE | ID: mdl-34280258

ABSTRACT

Asparaginase (ASNase) therapy has been a mainstay of acute lymphoblastic leukemia (ALL) protocols for decades and shows promise in the treatment of a variety of other cancers. To improve the efficacy of ASNase treatment, we used a CRISPR/Cas9-based screen to identify actionable signaling intermediates that improve the response to ASNase. Both genetic inactivation of Bruton's tyrosine kinase (BTK) and pharmacological inhibition by the BTK inhibitor ibrutinib strongly synergize with ASNase by inhibiting the amino acid response pathway, a mechanism involving c-Myc-mediated suppression of GCN2 activity. This synthetic lethal interaction was observed in 90% of patient-derived xenografts, regardless of the genomic subtype. Moreover, ibrutinib substantially improved ASNase treatment response in a murine PDX model. Hence, ibrutinib may be used to enhance the clinical efficacy of ASNase in ALL. This trial was registered at www.clinicaltrials.gov as # NCT02884453.


Subject(s)
Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Amino Acids/metabolism , Antineoplastic Agents/therapeutic use , Asparaginase/therapeutic use , Piperidines/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adenine/pharmacology , Adenine/therapeutic use , Agammaglobulinaemia Tyrosine Kinase/metabolism , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Asparaginase/pharmacology , Cell Line, Tumor , Humans , Mice , Piperidines/pharmacology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Signal Transduction/drug effects
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