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Blastic Plasmacytoid Dendritic Cell Neoplasms (BPDCN)
Published in Dongyou Liu, Tumors and Cancers, 2017
Molecularly, BPDCN is linked to multiple karyotypic abnormalities (e.g., chromosomes 5q [72%], 12p [64%], 13q [64%], 6q [50%], 15q [43%], and monosomy 9 [28%]) and genetic mutations involving 9p21.3 (CDKN2A/CDKN2B, 50%), 13q13.1-q14.3 (RB1, 43%), 12p13.2-p13.1 (CDKN1B, 64%), 13q11-q12 (LATS2), TET2 (36%–80%), ASXL1 (32%), NPM1 (20%), NRAS (20%), IKZF1 (20%), IKZF1-3 (20%), ZEB2 (16%), TP53 (14%), HOXB9 (4%), and UBE2G2 (4%) [4,5].
Molecular features, prognosis, and novel treatment options for pediatric acute megakaryoblastic leukemia
Published in Expert Review of Hematology, 2019
Federico De Marchi, Marito Araki, Norio Komatsu
The remaining genetic background of non-DS AMegL has been elusive, and 35% of the cases remain without known genetic alteration. Other less frequent, but reported, chromosomal alterations in non-DS AMegL include CALM–AF10 [54], t(9;11), +8, and +21, wherein these mutations may alter pathways involved in hematopoiesis. GATA2–HOXA9, MN1–FLI1, and NIPBL–HOXB9 fusion transcripts have also been reported [39], and a recent study showed that these three fusion genes, separate from CBFA2T3–GLIS2, are sufficient to cause overt leukemia in mice [55]. Genome-wide studies and larger cohorts are necessary to fully elucidate alteration frequencies and their roles in the development of the disease. Understanding the molecular basis of the disease will aid in the development of therapeutic agents, such as fusion, specific pathway, and kinase inhibitors that alone or in combination may result in better prognosis, which remains poor.
The role of tumor angiogenesis as a therapeutic target in colorectal cancer
Published in Expert Review of Anticancer Therapy, 2018
Francesca Battaglin, Alberto Puccini, Rossana Intini, Marta Schirripa, Alessandra Ferro, Francesca Bergamo, Sara Lonardi, Vittorina Zagonel, Heinz-Josef Lenz, Fotios Loupakis
Kopetz et al. investigated the changes in plasma cytokines and angiogenic factors (CAFs) in a phase II trial in previously untreated mCRC patients who underwent FOLFIRI plus bevacizumab treatment. In this study interleukin-8 levels at baseline were associated with a shorter PFS (11 vs. 15.1 months, p = 0.03) and several other CAFs, including FGF, hepatocyte growth factor (HGF), stromal-derived factor-1 (SDF-1) and macrophage chemoattractant protein-3 (MCP-3), were found to be increased prior to evidence of disease progression, suggesting that they may predict resistance to anti-VEGF therapy [83]. Bates et al. analyzed CRC tumor samples from the phase III E3200 trial to test the predictive value of VEGF165b, a VEGF splice isoform. Patients with a low level of VEGF165b seemed to benefit more from bevacizumab treatment, however, survival results were not statistically significant [84]. More recently, Carbone et al. demonstrated that patients affected by Homeobox B9 (HOXB9)-negative tumors had a significantly longer PFS compared with those with HOXB9-positive tumors when treated with a first-line bevacizumab-containing regimen (18.0 vs. 10.4 months, p = 0.048). HOXB9 is a highly conserved homeobox transcription factor gene which drives neoplastic transformation and tumor progression through an anti-apoptotic process and tumor cell invasion. The authors demonstrated, with preclinical and clinical data, that transcription factor HOXB9 modulates resistance of pancreatic and colorectal cancer to bevacizumab modulating a complex network of alternative pro-inflammatory and pro-angiogenic secreted factors [85]. A prospective validation of these promising results is highly anticipated.
Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma
Published in OncoImmunology, 2020
Joseph R. Podojil, Alexander P. Glaser, Dylan Baker, Elise T. Courtois, Damiano Fantini, Yanni Yu, Valerie Eaton, Santhosh Sivajothi, Mingyi Chiang, Arighno Das, Kimberly A. McLaughlin, Paul Robson, Stephen D. Miller, Joshua J. Meeks
After confirmation of the functional activity of our B7-H4 antibody, we investigated if anti-B7-H4 could modulate tumor development in the BBN bladder cancer model. Mice were given BBN for 4 months followed by normal drinking water during treatment with a species and isotype-matched control antibody, anti-PD-1, or anti-B7-H4 once weekly for four total treatments (Figure 5a). Treatment with the anti-B7-H4 antibody led to a decrease in the number of advanced tumors (50% stage 3 or greater compared to 70% in controls), and a significant increase in the number of CD8+ bladder-infiltrating T cells (Figure 5b,c). In contrast, anti-B7-H4 treatment decreased the number of Foxp3+ Tregs (Figure 5b,d), indicating that anti-B7-H4 treatment shifted the CD8+ T cell to Treg ratio in favor of an anti-tumor response (Supplemental Figure 3). While treatment of mice with anti-PD-1 or anti-B7-H4 did not alter the number of total splenic CD45hi cells, CD4+ T cells, or CD8+ T cells present within the spleen (Figure 5e), both anti-PD-1 and anti-B7-H4 treatments significantly increased the number of CD8+/IFN-γ+ cells present within the spleen compared to control Ab-treated mice (figure 5f). Total splenocytes from the treatment groups were activated ex vivo in the presence of anti-CD3 for 3 days to assess levels of cytokine secretion. Splenocytes from anti-B7-H4-treated mice secreted significantly higher levels of IFN-γ in response to anti-CD3 stimulation, as compared to T cells from control Ab or anti-PD-1 treated mice (Figure 5g). We also evaluated the gene expression profile of anti-B7-H4 treated mice, and found reestablishment of normal gene expression associated with urothelium differentiation. These changes included increased expression of bladder muscle/detrusor-related pathway transcripts, the urothelial differentiation transcript (uroplakin 3b), and decreased the expression of cell-cycle progression, mitosis, and cell-cycle checkpoint transcripts (Supplemental Figure 5). Most prominently, the response to B7-H4 was associated with decreased expression of the oncogenes Hoxb9, H19, and Egln3. The data also show metabolic changes suggestive of increased aerobic pathway usage, including the expression of Car2 (carbonic anhydrase), adh1 (alcohol dehydrogenase), and Pck1. These findings indicate that anti-B7-H4 treatment of BBN mice induced an increase in CD8+ T cell infiltration into the bladder and increased the level of IFN-γ secreted per splenic CD8+ T cell, while decreasing the number of Tregs present within the bladder.