Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases

Dasgupta, Yashodhara; Koptyra, Mateusz; Hoser, Grazyna; Kantekure, Kanchan; Roy, Darshan; Górnicka, Barbara; Nieborowska‐Skorska, Margaret; Bolton-Gillespie, Elisabeth; Cerny-Reiterer, Sabine; Müschen, Markus; Valent, Peter; Wasik, Mariusz A.; Richardson, Christine; Hantschel, Oliver; Kuip, Heiko van der; Stokłosa, Tomasz; Skórski, Tomasz

doi:10.1182/blood-2015-11-681171

Cited by 35 publications

(33 citation statements)

References 78 publications

(91 reference statements)

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“…This complex is important for TNF‐induced apoptosis, which is mediated through Fas/FasL interaction . Three additional genes downregulated in BLT1 −/− apoptotic neutrophils, Abl1 , Bax , and Caspase 3 , are downstream of DISC signaling . We next confirmed the decreased expression of DISC components and downstream effectors in BLT1 −/− apoptotic BMN compared to WT both in vitro and in vivo using flow cytometry (Figure ) .…”

Section: Resultsmentioning

confidence: 59%

“…40 Three additional genes downregulated in BLT1 −/− apoptotic neutrophils, Abl1, Bax, and Caspase 3, are downstream of DISC signaling. 41,42 We next confirmed the decreased expression of DISC components and downstream effectors in BLT1 −/− apoptotic BMN compared to WT both in vitro and in vivo using flow cytometry (Figure 4). FasL expression was used to assess DISC formation, while CD36, important for apoptotic cell recognition, efferocytosis, and caspase-3 activation, was used to determine the downstream effects of DISC formation.…”

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confidence: 57%

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Leukotriene B4 receptor BLT1 signaling is critical for neutrophil apoptosis and resolution of experimental Lyme arthritis

et al. 2019

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Eicosanoids are powerful mediators of inflammation and are known to drive both the progression and regression of arthritis. We previously reported the infection of C3H 5-lipoxygenase (LO)-deficient mice with Borrelia burgdorferi results in prolonged nonresolving Lyme arthritis. Here we define the role of the 5-LO metabolite leukotriene (LT)B 4 and its high-affinity receptor, BLT1, in this response. C3H and C3H BLT1 −/− mice were infected with B. burgdorferi and arthritis progression was monitored by ankle swelling over time. Similar to 5-LO −/− mice, BLT1 −/− mice developed nonresolving Lyme arthritis characterized by increased neutrophils in the joint at later time points than WT mice, but with fewer apoptotic (caspase-3 + ) neutrophils. In vitro, BLT1 −/− neutrophils were defective in their ability to undergo apoptosis due to the lack of LTB 4 -mediated down-regulation of cAMP, subsequent failure to induce Death-Inducing Signaling Complex (DISC) components, and decreased FasL and CD36 expression. Inhibition of adenylyl cyclase with SQ 22,536 restored BLT1 −/− BMN apoptosis, FasL and CD36 expression, and clearance by macrophages. We conclude that LTB4/BLT1 signaling has an unexpected critical role in mediating neutrophil apoptosis via the down-regulation of cAMP. Loss of BLT1 signaling led to defective clearance of neutrophils from the inflamed joint and failed arthritis resolution. K E Y W O R D S BLT1, efferocytosis, Lyme arthritis, resolution

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Section: Resultsmentioning

confidence: 59%

mentioning

confidence: 57%

Leukotriene B4 receptor BLT1 signaling is critical for neutrophil apoptosis and resolution of experimental Lyme arthritis

et al. 2019

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“…However, the binding affinity could be different due to different conformations between the two normal isoforms and the BCR-ABL protein, but the extent of such difference is currently unknown. Meanwhile, normal ABL1 protein was found to act as a tumor suppressor when co-expressed with BCR-ABL, while loss of expression of normal ABL1 results in higher aggressiveness of the disease and reduced sensitivity to Imatinib-like TKIs, although we are not sure which isoform is primarily responsible for this effect either 77,78 . These results reinforce the fact that potentially important splicing changes in ABL isoforms can influence the therapeutic effect of Imatinib-like TKIs, which require further investigation in future studies.…”

Section: Discussionmentioning

confidence: 94%

In silico analysis of alternative splicing on drug-target gene interactions

Mishra

Davuluri

2020

Sci Rep

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full-length protein-coding transcripts, highlighting the complexity of the total proteome that can be expressed by different cells and tissues in the human body. Numerous studies have noted the functional importance of maintaining a coordinated regulation of alternative events in various biological processes, such as tissue development and aging 7-9. Isoforms of a gene often appear to have different, sometimes even opposite functions, and are tightly regulated to express in a context-specific manner. Conversely, a disruption of such coordinated regulation is often linked to diseases, such as cancer. A recent large transcriptome-wide study revealed that ~19% genes consistently undergo isoform switching (context-dependent differential usage of isoforms) that potentially have functional consequences across 12 solid cancer types 10. Such genes with isoform switching were previously found to relate to all hallmarks of cancer, in particular apoptosis and metastasis 11,12. One best example of such aberrant isoform switching in angiogenesis is VEGFA gene, where a switching from anti-angiogenic isoform VEGFA 165 b to pro-angiogenic splice variant VEGFA 165 is observed in multiple types of cancers 13-17. Another apoptosis-related example is the BCL2L1 gene, where a switching from pro-apoptotic short isoform Bcl-xs to anti-apoptotic long splice variant Bcl-xl enable cancer to bypass programmed cell death 18-20. Examples for metastasis-enabling isoform switching include cell surface adhesion receptors, such as CD44 21 and CDH1 (E-cadherin) 22 ; growth factor receptors, such as FGFR2 23 and TGFBR2 24 ; as well as other proteins that induce EMT and confer enhanced invasiveness/motility of cells, such as the Rac1b isoform of RAC1 gene 25-27 and a short-form, constitutively active isoform of RON gene (RonΔ165) 28. Importantly, the RON gene simultaneously produces other tumor-promoting or tumor-opposing isoforms involved in different pathways under different conditions 5. Meanwhile, the aberrant splicing of RAC1 gene has also been linked with multiple other cancer hallmarks, including proliferation, genome instability and inflammation 12. Another aberrant splicing example responsible for sustained proliferative signaling is BRAF gene, as alternative isoforms of wild-type and V600E mutant affect its kinase domain and may confer resistance to treatment 29,30. For isoforms related to evading growth suppressors, human TP53 itself serves as a perfect example, as many splice variants exists for this well-studied tumor suppressor, some of which are dominant-negative hampering anti-tumor function of wild-type p53 31,32. In addition, alternatively spliced, dominant negative isoforms of human telomerase gene TERT were identified in multiple cancers 33,34 , while splice variants for HLA-G protein were found on surface of tumor cells that enhance immune evasion 35. The above examples suggest that disease-causing splice variants, or aberrant isoforms, not only can function as important biomarkers but also have the potential of becoming succes...

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“…These domains are crucial for ABL1 activity, as its subcellular localization defines effects of its activation. In the cytoplasm, it increases proliferation rate and survival of cells, while in the nucleus it leads to cell cycle arrest and cell death promotion [66]. At least one normal ABL1 allele is usually present in cells expressing BCR-ABL1, acting as a tumor suppressor, as its knockout in CML CP cells leads to increased survival of cells in vitro and development of much more aggressive leukemia in mice [66].…”

Section: Similarities and Differences In Signaling Mediated By P190 Amentioning

confidence: 99%

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

Komorowski

Fidyt

Patkowska

et al. 2020

IJMS

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Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 9 and ABL proto-oncogene 1 (ABL1) gene on chromosome 22. The fusion gene, BCR-ABL1, is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the BCR gene, different isoforms of BCR-ABL1 exist, with p210 and p190 being the most prevalent. P210 isoform is the hallmark of chronic myeloid leukemia (CML), while p190 isoform is expressed in majority of Ph-positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) cases. The crucial component of treatment protocols of CML and Ph+ B-ALL patients are tyrosine kinase inhibitors (TKIs), drugs which target both BCR-ABL1 isoforms. While TKIs therapy is successful in great majority of CML patients, Ph+ B-ALL often relapses as a drug-resistant disease. Recently, the high-throughput genomic and proteomic analyses revealed significant differences between CML and Ph+ B-ALL. In this review we summarize recent discoveries related to differential signaling pathways mediated by different BCR-ABL1 isoforms, lineage-specific genetic lesions, and metabolic reprogramming. In particular, we emphasize the features distinguishing Ph+ B-ALL from CML and focus on potential therapeutic approaches exploiting those characteristics, which could improve the treatment of Ph+ B-ALL.

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Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases

Abstract: Key Points Normal ABL1 is a tumor suppressor in BCR-ABL1–induced leukemia. Allosteric stimulation of the normal ABL1 kinase activity enhanced the antileukemia effect of ABL1 tyrosine kinase inhibitors.

Cited by 35 publications

References 78 publications

Leukotriene B4 receptor BLT1 signaling is critical for neutrophil apoptosis and resolution of experimental Lyme arthritis

Leukotriene B4 receptor BLT1 signaling is critical for neutrophil apoptosis and resolution of experimental Lyme arthritis

In silico analysis of alternative splicing on drug-target gene interactions

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

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