Interference with pre-B-cell receptor signaling offers a therapeutic option for TCF3-rearranged childhood acute lymphoblastic leukemia

Veer, Arian van der; Velden, Vincent H.J. van der; Willemse, Marieke E.; Hoogeveen, Patricia G.; Petricoin, Emanuel F.; Beverloo, H. Berna; Escherich, Gabriele; Horstmann, Martin; Pieters, Rob; Boer, Monique L. den

doi:10.1038/bcj.2014.5

Cited by 18 publications

(12 citation statements)

References 23 publications

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“…Despite recent reports on the efficacy of the BTK inhibitor ibrutinib in pre-BCR + ALL, both Igμ-KO and PRT318 did not interfere with BTK signaling activity, suggesting that BTK is dispensable for the pro-proliferating effect of the pre-BCR in B-ALL. 24,14 Accordingly, the reported effective concentrations of ibrutinib in pre-BCR + ALL are considerably higher than in established BTK-dependent B-cell malignancies, indicating that ibrutinib might exert its effects in pre-BCR + ALL through the inhibition of alternative targets. 24,54,55 …”

Section: Discussionmentioning

confidence: 99%

“…14 Whether inhibition of pre-BCR signaling using, for example, SYK inhibitors is more broadly applicable across B-ALL subsets, as suggested by earlier studies 21–23 , or restricted to pre-BCR + subsets of patients based on more recent studies, remains controversial, given these discrepant data. 14,20,24 This has major impact on the conceptualization of future clinical trials, which could be restricted to pre-BCR + patient subsets or not.…”

Section: Introductionmentioning

confidence: 99%

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Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition

et al. 2016

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Pre-BCR signaling and SYK recently were introduced as therapeutic targets for patients with B-cell acute lymphoblastic leukemia (B-ALL), but the importance of this pathway in B-ALL subsets and mechanism of downstream signaling have not fully been elucidated. Here, we provide new detailed insight into the mechanism of pre-BCR signaling in B-ALL. We compared the effects of pharmacologic and genetic disruption of pre-BCR signaling in vitro and in mouse models for B-ALL, demonstrating exquisite dependency of pre-BCR+ B-ALL, but not other B-ALL subsets, on this signaling pathway. We demonstrate that SYK, PI3K/AKT, FOXO1, and MYC are important downstream mediators of pre-BCR signaling in B-ALL. Furthermore, we define a characteristic immune phenotype and gene expression signature of pre-BCR+ ALL to distinguish them from other B-ALL subsets. These data provide comprehensive new insight into pre-BCR signaling in B-ALL and corroborate pre-BCR signaling and SYK as promising new therapeutic targets in pre-BCR+ B-ALL.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition

et al. 2016

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“…This group includes the ALL subset with TCF3-PBX1 rearrangement, which is selectively sensitive to ibrutinib. 69 Treatment with the dual ABL1/BTK-SRC kinase inhibitor dasatinib induced leukemia regression and extended overall survival of nonobese diabetic/severe combined immunodeficiency mice that were transplanted with patient-derived pre-BCR 1 ALL cells. 64 In up to 50% of pre-BCR 1 ALL cells, the leukemia cells carry an activating lesion of the homeodomain transcription factor PBX1, mostly through TCF3-PBX1 rearrangement 66,68 and in some cases through duplication of a fragment at 1q23 encompassing PBX1.…”

Section: Identification Of a Pre-bcr-dependent Subset Of Human Allmentioning

confidence: 99%

Rationale for targeting the pre–B-cell receptor signaling pathway in acute lymphoblastic leukemia

Müschen

2015

Blood

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Inhibitors of B-cell receptor (BCR) and pre-BCR signaling were successfully introduced into patient care for various subtypes of mature B-cell lymphoma (eg, ibrutinib, idelalisib). Acute lymphoblastic leukemia (ALL) typically originates from pre-B cells that critically depend on survival signals emanating from a functional pre-BCR. However, whether patients with ALL benefit from treatment with (pre-) BCR inhibitors has not been explored. Recent data suggest that the pre-BCR functions as tumor suppressor in the majority of cases of human ALL. However, a distinct subset of human ALL is selectively sensitive to pre-BCR antagonists.

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“…31,32 Ibrutinib was recently suggested as a potential therapeutic option for pre-BCR 1 or TCF3-rearranged ALL. 17,33 However, another study reported that t(1;19)-ALL is sensitive to the SRC/ABL/BTK inhibitor dasatinib but not to ibrutinib or BTK knockdown. 19 Here, we explore the preclinical therapeutic potential of ibrutinib in ALL and mechanism of its action.…”

Section: Introductionmentioning

confidence: 99%

Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK

Kim

Hurtz

Koehrer

et al. 2017

Blood

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Interference with pre-B-cell receptor signaling offers a therapeutic option for TCF3-rearranged childhood acute lymphoblastic leukemia

Cited by 18 publications

References 23 publications

Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition

Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition

Rationale for targeting the pre–B-cell receptor signaling pathway in acute lymphoblastic leukemia

Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK

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