Tyrosine kinase inhibitor resistance in de novo BCR::ABL1-positive BCP-ALL beyond kinase domain mutations

TY - JOUR

T1 - Tyrosine kinase inhibitor resistance in de novo BCR::ABL1-positive BCP-ALL beyond kinase domain mutations

AU - van Outersterp, Inge

AU - Boer, Judith M

AU - van de Ven, Cesca

AU - Reichert, Caitlin E J

AU - Boeree, Aurelie

AU - Kruisinga, Brian

AU - de Groot-Kruseman, Hester A

AU - Escherich, Gabriele

AU - Sijs-Szabo, Aniko

AU - Rijneveld, Anita W

AU - den Boer, Monique L

N1 - © 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

PY - 2024/4/23

Y1 - 2024/4/23

N2 - A better understanding of ABL1 kinase domain mutation-independent causes of tyrosine kinase inhibitor (TKI) resistance is needed for BCR::ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Although TKIs have dramatically improved outcomes, a subset of patients still experiences relapsed or refractory disease. We aimed to identify potential biomarkers of intrinsic TKI resistance at diagnosis in samples from 32 pediatric and 19 adult patients with BCR::ABL1-positive BCP-ALL. Reduced ex vivo imatinib sensitivity was observed in cells derived from newly diagnosed patients who relapsed after combined TKI and chemotherapy treatment compared with cells derived from patients who remained in continuous complete remission. We observed that ex vivo imatinib resistance was inversely correlated with the amount of (phosphorylated) BCR::ABL1/ABL1 protein present in samples that were taken at diagnosis without prior TKI exposure. This suggests an intrinsic cause of TKI resistance that is independent of functional BCR::ABL1 signaling. Simultaneous deletions of IKZF1 and CDKN2A/B and/or PAX5 (IKZF1plus), as well as deletions of PAX5 alone, were related to ex vivo imatinib resistance. In addition, somatic lesions involving ZEB2, SETD2, SH2B3, and CRLF2 were associated with reduced ex vivo imatinib sensitivity. Our data suggest that the poor prognostic value of IKZF1(plus) deletions is linked to intrinsic mechanisms of TKI resistance other than ABL1 kinase domain mutations in newly diagnosed pediatric and adult BCR::ABL1-positive BCP-ALL.

AB - A better understanding of ABL1 kinase domain mutation-independent causes of tyrosine kinase inhibitor (TKI) resistance is needed for BCR::ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Although TKIs have dramatically improved outcomes, a subset of patients still experiences relapsed or refractory disease. We aimed to identify potential biomarkers of intrinsic TKI resistance at diagnosis in samples from 32 pediatric and 19 adult patients with BCR::ABL1-positive BCP-ALL. Reduced ex vivo imatinib sensitivity was observed in cells derived from newly diagnosed patients who relapsed after combined TKI and chemotherapy treatment compared with cells derived from patients who remained in continuous complete remission. We observed that ex vivo imatinib resistance was inversely correlated with the amount of (phosphorylated) BCR::ABL1/ABL1 protein present in samples that were taken at diagnosis without prior TKI exposure. This suggests an intrinsic cause of TKI resistance that is independent of functional BCR::ABL1 signaling. Simultaneous deletions of IKZF1 and CDKN2A/B and/or PAX5 (IKZF1plus), as well as deletions of PAX5 alone, were related to ex vivo imatinib resistance. In addition, somatic lesions involving ZEB2, SETD2, SH2B3, and CRLF2 were associated with reduced ex vivo imatinib sensitivity. Our data suggest that the poor prognostic value of IKZF1(plus) deletions is linked to intrinsic mechanisms of TKI resistance other than ABL1 kinase domain mutations in newly diagnosed pediatric and adult BCR::ABL1-positive BCP-ALL.

KW - Adult

KW - Humans

KW - Child

KW - Imatinib Mesylate/pharmacology

KW - Fusion Proteins, bcr-abl/metabolism

KW - Tyrosine Kinase Inhibitors

KW - Protein Kinase Inhibitors/pharmacology

KW - Mutation

KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis

U2 - 10.1182/bloodadvances.2023012162

DO - 10.1182/bloodadvances.2023012162

M3 - SCORING: Journal article

C2 - 38386975

VL - 8

SP - 1835

EP - 1845

JO - BLOOD ADV

JF - BLOOD ADV

SN - 2473-9529

IS - 8

ER -