The antiapoptotic gene A1/BFL1 is a WT1 target gene that mediates granulocytic differentiation and resistance to chemotherapy

Simpson, Lesley A.; Burwell, Emily A.; Thompson, Kida A.; Shahnaz, Samira; Chen, Allen; Loeb, David M.

doi:10.1182/blood-2005-10-4025

Cited by 47 publications

(43 citation statements)

References 27 publications

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“…In addition to NFB, other transcription factors have been implicated in the transcriptional regulation of Bfl-1. These include all-trans retinoic acids in leukemia cells 401 , retinoic X receptor agonists in naïve T lymphocytes 402 , and the transcription factors WT-1 403 and PU.1 404 . On the other hand, Bfl-1 transcription has also been observed to be blocked by the transcription factor Blimp-1 in plasma cells 405 .…”

Section: The Regulation Of Bfl-1mentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Section: The Regulation Of Bfl-1mentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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“…44 In addition to antiapoptotic genes, WT1 directly modulates the expression of genes that encode components of the cell cycle apparatus, such as cyclin E, which co-regulates the G1/S-phase transition. 42 The recently described AML-related CTA cyclin A1 has also been implicated in the G1/S-phase regulation. 33 Other LAAs, including AurA, 32 cyclin B1, 45 M-phase phosphoprotein 11 (MPP11), 36 NuSAP1, 46 SSX2IP 36 and RHAMM, 36 are predominantly involved in regulating the G2/M transition or the mitotic phase of the cell cycle.…”

Section: Criterion 3: Oncogenicitymentioning

confidence: 99%

“…These studies, including WT1 peptide and WT1-targeted dendritic cell vaccine trials, have unequivocally established that CD8 þ T-cell immune responses specific to WT1 can be induced by active immunization in a substantial number of AML patients. 14 In those patients, multiple WT1 CTL epitopes have been recognized as immunogenic (including WT1 [37][38][39][40][41][42][43][44][45] , WT1 [126][127][128][129][130][131][132][133][134] , WT1 [187][188][189][190][191][192][193][194][195] and WT1 [235][236][237][238][239][240][241][242][243] ), demonstrating the excellent in vivo immunostimulatory potential of WT1 (Table 1). 14,72 This is further supported by the capacity to induce WT1-specific CD4 þ helper T-cell immunity in patients with AML through active immunization.…”

Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 99%

“…87 These findings were corroborated by the later work of Rezvani et al, 73 who observed spontaneous T-cell responses to PR1 and WT1 [126][127][128][129][130][131][132][133][134] in two out of eight patients before immunization with a combined PR1/WT1 peptide vaccine. 73 In a separate study, the same group found that such CTL responses were not limited to the immunodominant WT1 [126][127][128][129][130][131][132][133][134] epitope, but could also be directed against other HLA-A*0201-restricted WT1-derived epitopes (WT1 [37][38][39][40][41][42][43][44][45] , WT1 [187][188][189][190][191][192][193][194][195] and WT1 [235][236][237][238][239][240][241][242][243] ). 88 A similar observation was made regarding PRAME, which is known to contain at least four different HLA-A*0201-restricted epitopes that can be naturally recognized (PRA …”

Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 99%

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Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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The graft-versus-leukemia effect of allogeneic hematopoietic stem cell transplantation (HSCT) has shown that the immune system is capable of eradicating acute myeloid leukemia (AML). This knowledge, along with the identification of the target antigens against which antileukemia immune responses are directed, has provided a strong impetus for the development of antigen-targeted immunotherapy of AML. The success of any antigen-specific immunotherapeutic strategy depends critically on the choice of target antigen. Ideal molecules for immune targeting in AML are those that are: (1) leukemia-specific; (2) expressed in most leukemic blasts including leukemic stem cells; (3) important for the leukemic phenotype; (4) immunogenic; and (5) clinically effective. In this review, we provide a comprehensive overview on AML-related tumor antigens and assess their applicability for immunotherapy against the five criteria outlined above. In this way, we aim to facilitate the selection of appropriate target antigens, a task that has become increasingly challenging given the large number of antigens identified and the rapid pace at which new targets are being discovered. The information provided in this review is intended to guide the rational design of future antigen-specific immunotherapy trials, which will hopefully lead to new antileukemia therapies with more selectivity and higher efficacy.

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“…3 Our laboratory has investigated the hypothesis that different WT1 isoforms can have distinct effects on tumorigenesis. We found that induction of WT1 (ϪEx5/ϪKTS) in mammary epithelial cells causes a cell cycle arrest and expression of genes such as albumin associated with a differentiated phenotype, whereas induction of WT1 (ϩEx5/ϩKTS) results in an epithelial-to-mesenchymal transition and up-regulation of proliferation-associated genes such as B-raf (13). In the course of these investigations, we also found that WT1 (ϩEx5/ϩKTS) up-regulates vascular endothelial growth factor (VEGF) in these cells.…”

mentioning

confidence: 96%