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

Kim, Ekaterina; Hurtz, Christian; Koehrer, Stefan; Wang, Zhiqiang; Balasubramanian, Sriram; Chang, Betty; Müschen, Markus; Davis, R. Eric; Burger, Jan A.

doi:10.1182/blood-2016-06-722900

Cited by 67 publications

(59 citation statements)

References 57 publications

(64 reference statements)

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“…E-selectin engagement promotes the assembly of functional IFN-gR2 by driving membrane translocation of IFN-gR2 via BTK kinase. BTK is a member of the Tec family and is involved in many signaling pathways via E-selectin (Mueller et al, 2010), B cell receptor (BCR) (Kim et al, 2017), TLR , or chemokine receptors CXCR4 (de Gorter et al, 2007). BTKdeficient mice have a leukocyte recruitment defect in complex disease models (Mangla et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation-Mediated IFN-γR2 Membrane Translocation Is Required to Activate Macrophage Innate Response

et al. 2018

Cell

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Section: Discussionmentioning

confidence: 99%

Phosphorylation-Mediated IFN-γR2 Membrane Translocation Is Required to Activate Macrophage Innate Response

et al. 2018

Cell

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“…24 Other kinases with substantially reduced capture in drug treated cells included LCK, FYN, LYN, FGR, SRC, CSK, TEC, BLK and RIPK2, which are all known to be directly inhibited by both ibrutinib and dasatinib. 23,25,26 We also observed more modest reductions in capture of a number of other kinases including ERK1 and 2, PKCb and IKKb ( Figure 1D) which are not known as direct targets of ibrutinib/dasatinib but are likely to be modulated as a response to upstream effects. Reduced capture of MEK1 and MEK2 was consistent with the observed reduction of phosphorylation of the MEK1/2 substrates ERK1/2 detected by immunoblotting ( Supplementary Figure 1).…”

Section: Validation Of Kinobeads For the Analysis Of Malignant B Cellsmentioning

confidence: 87%

Kinobead Profiling Reveals Reprogramming of B-cell Receptor Signaling in Response to Therapy Within Primary Chronic Lymphocytic Leukemia Cells

Linley

Griffin

Cicconi

et al. 2019

Preprint

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+44(0)151 794 5310 Running head: Therapy brings about BCR signal changes. Key points1. sIgM signaling patterns alter following in vivo therapy using either chemoimmunotherapy or ibrutinib. Kinobeads provide a novel method for high-resolution investigation of signaling in primary CLL cells. AbstractInduction of signaling via cell surface receptor activation is a critical driver of CLL pathobiology, especially via the B-cell receptor (BCR), which promotes tumor survival and progression. The vital nature of BCR signaling has been recognized through the development of kinase inhibitors (KI), most notably ibrutinib, that target key nodes within this pathway. Current efforts to monitor signaling investigate expression of a highly confined series of kinases and phosphoproteins. While generating key insights, full appreciation of their wider significance to malignant pathology and therapy response remains an unresolved issue. Here, we describe a kinobead-based protocol, used in conjunction with mass-spectrometry (MS) or immunoblotting, to study surface-IgM (sIgM) signaling within primary CLL cells. Employing this approach, we isolated a 'fingerprint' of over 30 kinases which displayed unique, patient-specific response to sIgM stimulation, and which displayed greater activation change in CLL cells from patients who had undergone prior chemoimmunotherapy (CIT) compared to those from untreated/treatment-naïve patients. Matched sample analysis of ARCTIC/AdMIRe clinical trial patients revealed the unique nature of the kinome response was present at the intra-patient level, while longitudinal profiling of IcICLLe trial patients supported this as well as showing our finding related to ibrutinib therapy. Refinement of the kinome fingerprint determined 4 kinases linked to proliferation found to be present to a significantly higher level within previously treated patient cells. Proliferation assays confirmed that these patients possess higher proliferative capacity, implying alterations of signaling resulting in promoting of biological processes critical to malignant cells. Collectively, these data represent the first comprehensive investigation into BCR signaling response within CLL, where our probing of kinase active sites reveals unique evidence of adaptive reprogramming in response to therapy.

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“…The results observed in vitro showed a gene inhibition effect, and in vivo, tumor regression [34]. Moreover, the CRISPR-Cas9 editing tool revealed targets for Ibrutinib therapy intended to deactivate the pre B cell receptor signal in acute lymphoblastic leukemia, such as B lymphocyte kinase and Bruton's tyrosine kinase [35].…”

Section: Medicinementioning

confidence: 99%

Review. Development, Applications, Benefits, Challenges and Limitations of the New Genome Engineering Technique. An Update Study

Crauciuc

Tripon

Gheorghiu

et al. 2017

Acta Medica Marisiensis

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We assume that the CRISPR Cas9 theory must be delimited by applicability, because the consequences of long term DNA manipulation remain unknown. Moreover, the irreversibility of this procedure should instigate researchers to reserved opinions. Usefulness as well as benefits of CRISPR Cas9 made it one of the most popular and used genome editing technique. But with its huge potential, ethical and safety concerns emerge. Therefore, before continuing research in this direction we should have a well organized system that is able to make that differentiation between research and reproduction. However we truly believe in the future of genetic engineering and with the CRISPR-Cas9 system we expect that the opportunity of treating now so called incurable diseases arises. Time is all we need.

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

Abstract: Key Points In B-ALL, cells that express a functional pre-BCR ibrutinib abrogate leukemia cell growth in vitro and in vivo. Effects of ibrutinib in B-ALL not only are mediated through inhibition of BTK but also involve BLK inhibition.

Cited by 67 publications

References 57 publications

Phosphorylation-Mediated IFN-γR2 Membrane Translocation Is Required to Activate Macrophage Innate Response

Phosphorylation-Mediated IFN-γR2 Membrane Translocation Is Required to Activate Macrophage Innate Response

Kinobead Profiling Reveals Reprogramming of B-cell Receptor Signaling in Response to Therapy Within Primary Chronic Lymphocytic Leukemia Cells

Review. Development, Applications, Benefits, Challenges and Limitations of the New Genome Engineering Technique. An Update Study

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