29 research outputs found
Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia
Cancer testis antigens (CTA) provide attractive targets for cancer-specific immunotherapy.
Although CTA genes are expressed in some normal tissues, such as the testis,
this immunologically protected site lacks MHC I expression and as such, does not
present self antigens to T cells. To date, CTA genes have been shown to be expressed
in a range of solid tumors via demethylation of their promoter CpG islands, but rarely
in chronic myeloid leukemia (CML) or other hematologic malignancies
Methylation status of Wnt signaling pathway genes affects the clinical outcome of Philadelphia-positive acute lymphoblastic leukemia
The clinical significance of aberrant promoter methylation of the
canonical Wnt pathway antagonist genes (sFRP1, sFRP2, sFRP4,
sFRP5, Wif1, Dkk3, and Hdpr1) and also putative tumor-suppressor
gene Wnt5a, belonging to the non-canonical Wnt signaling pathway,
was investigated in a large series of 75 patients with Philadelphia
chromosome-positive acute lymphoblastic leukemia by methylationspecific
polymerase chain reaction. At least one methylated gene
was observed in cells from 66% (49/75) of patients (methylated
group). Disease-free survival and overall survival at 9 years were 51
and 40%, respectively, for the unmethylated group and 3 and 2%,
respectively, for the methylated group (both P < 0.0001). Multivariate
analysis demonstrated that the Wnt methylation profile was an
independent prognostic factor predicting disease-free survival
(P = 0.007) and overall survival (P = 0.039). Abnormal DNA methylation
of promoter-associated CpG islands in the Wnt signaling pathway is
very common in Philadelphia chromosome-positive acute lymphoblastic
leukemia and potentially defines subgroups with distinct
clinical characteristics
Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia.
Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL
J-PLUS: The javalambre photometric local universe survey
ABSTRACT: TheJavalambrePhotometric Local UniverseSurvey (J-PLUS )isanongoing 12-band photometricopticalsurvey, observingthousands of squaredegrees of theNorthernHemispherefromthededicated JAST/T80 telescope at the Observatorio Astrofísico de Javalambre (OAJ). The T80Cam is a camera with a field of view of 2 deg2 mountedon a telescopewith a diameter of 83 cm, and isequippedwith a uniquesystem of filtersspanningtheentireopticalrange (3500–10 000 Å). Thisfiltersystemis a combination of broad-, medium-, and narrow-band filters, optimallydesigned to extracttherest-framespectralfeatures (the 3700–4000 Å Balmer break region, Hδ, Ca H+K, the G band, and the Mg b and Ca triplets) that are key to characterizingstellartypes and delivering a low-resolutionphotospectrumforeach pixel of theobservedsky. With a typicaldepth of AB ∼21.25 mag per band, thisfilter set thusallowsforanunbiased and accuratecharacterization of thestellarpopulation in our Galaxy, itprovidesanunprecedented 2D photospectralinformationforall resolved galaxies in the local Universe, as well as accuratephoto-z estimates (at the δ z/(1 + z)∼0.005–0.03 precisionlevel) formoderatelybright (up to r ∼ 20 mag) extragalacticsources. Whilesomenarrow-band filters are designedforthestudy of particular emissionfeatures ([O II]/λ3727, Hα/λ6563) up to z < 0.017, theyalsoprovidewell-definedwindowsfortheanalysis of otheremissionlines at higherredshifts. As a result, J-PLUS has thepotential to contribute to a widerange of fields in Astrophysics, both in thenearbyUniverse (MilkyWaystructure, globular clusters, 2D IFU-likestudies, stellarpopulations of nearby and moderate-redshiftgalaxies, clusters of galaxies) and at highredshifts (emission-line galaxies at z ≈ 0.77, 2.2, and 4.4, quasi-stellarobjects, etc.). Withthispaper, wereleasethefirst∼1000 deg2 of J-PLUS data, containingabout 4.3 millionstars and 3.0 milliongalaxies at r < 21mag. With a goal of 8500 deg2 forthe total J-PLUS footprint, thesenumbers are expected to rise to about 35 millionstars and 24 milliongalaxiesbytheend of thesurvey.Funding for the J-PLUS Project has been provided by the Governments of Spain and Aragón through the Fondo de Inversiones de Teruel, the Spanish Ministry of Economy and Competitiveness (MINECO; under grants AYA2017-86274-P, AYA2016-77846-P, AYA2016-77237-C3-1-P, AYA2015-66211-C2-1-P, AYA2015-66211-C2-2, AYA2012-30789, AGAUR grant SGR-661/2017, and ICTS-2009-14), and European FEDER funding (FCDD10-4E-867, FCDD13-4E-2685
WNT5A, a putative tumour suppressor of lymphoid malignancies, is inactivated by aberrant methylation in acute lymphoblastic leukaemia
Wnt5a is a member of the Wnt family of proteins that signals through the non-canonical
Wnt/Ca2+ pathway to suppress cyclin D1 expression and negatively regulate B cell proliferation
suggesting that it acts as an tumour suppressor for lymphoid leukemogenesis.
Although canonical Wnt pathway is a ‘hot spot’ for methylation in acute lymphoblastic leukaemia
(ALL), the role of Wnt5a abnormalities has never been evaluated in this clinical setting.
The methylation status of the WNT5A promoter was analysed by methylation-specific
PCR (MSP) and sequencing in six ALL-derived cell lines (TOM-1, NALM-20, MY, LOUCY, JURKAT
and TANOUE) and in 307 ALL patients. WNT5A and CYCLIN D1 expressions were
assessed by quantitative RT-PCR. We observed WNT5A hypermethylation in all cell lines
and in cells from 43% (132/307) of ALL patients. WNT5A methylation was associated with
decreased WNT5A mRNA expression (P < 0.001) and this expression was restored after
exposure to the demethylating agent 5-Aza-20-deoxycytidine. Moreover, WNT5A hypermethylation
correlated with upregulation of CYCLIN D1 expression (P = 0.002). Disease-free
survival (DFS) and overall survival (OS) at 13 and 14 years, respectively, were 59% and
53% for unmethylated patients and 28% and 31% for hypermethylated patients
(P = 0.0003 and P = 0.003). Multivariate analysis demonstrated that WNT5A methylation
was an independent prognostic factor predicting DFS (P = 0.003) and OS (P = 0.04). We have
demonstrated that WNT5A, a putative tumour suppressor gene in ALL, is silenced by methylation
in this disease and that this epigenetic event is associated with upregulation of
CYCLIN D1 expression and confers poor prognosis in this group of patients
WNT5A, a putative tumour suppressor of lymphoid malignancies, is inactivated by aberrant methylation in acute lymphoblastic leukaemia
Wnt5a is a member of the Wnt family of proteins that signals through the non-canonical
Wnt/Ca2+ pathway to suppress cyclin D1 expression and negatively regulate B cell proliferation
suggesting that it acts as an tumour suppressor for lymphoid leukemogenesis.
Although canonical Wnt pathway is a ‘hot spot’ for methylation in acute lymphoblastic leukaemia
(ALL), the role of Wnt5a abnormalities has never been evaluated in this clinical setting.
The methylation status of the WNT5A promoter was analysed by methylation-specific
PCR (MSP) and sequencing in six ALL-derived cell lines (TOM-1, NALM-20, MY, LOUCY, JURKAT
and TANOUE) and in 307 ALL patients. WNT5A and CYCLIN D1 expressions were
assessed by quantitative RT-PCR. We observed WNT5A hypermethylation in all cell lines
and in cells from 43% (132/307) of ALL patients. WNT5A methylation was associated with
decreased WNT5A mRNA expression (P < 0.001) and this expression was restored after
exposure to the demethylating agent 5-Aza-20-deoxycytidine. Moreover, WNT5A hypermethylation
correlated with upregulation of CYCLIN D1 expression (P = 0.002). Disease-free
survival (DFS) and overall survival (OS) at 13 and 14 years, respectively, were 59% and
53% for unmethylated patients and 28% and 31% for hypermethylated patients
(P = 0.0003 and P = 0.003). Multivariate analysis demonstrated that WNT5A methylation
was an independent prognostic factor predicting DFS (P = 0.003) and OS (P = 0.04). We have
demonstrated that WNT5A, a putative tumour suppressor gene in ALL, is silenced by methylation
in this disease and that this epigenetic event is associated with upregulation of
CYCLIN D1 expression and confers poor prognosis in this group of patients
Methylation status of Wnt signaling pathway genes affects the clinical outcome of Philadelphia-positive acute lymphoblastic leukemia
The clinical significance of aberrant promoter methylation of the
canonical Wnt pathway antagonist genes (sFRP1, sFRP2, sFRP4,
sFRP5, Wif1, Dkk3, and Hdpr1) and also putative tumor-suppressor
gene Wnt5a, belonging to the non-canonical Wnt signaling pathway,
was investigated in a large series of 75 patients with Philadelphia
chromosome-positive acute lymphoblastic leukemia by methylationspecific
polymerase chain reaction. At least one methylated gene
was observed in cells from 66% (49/75) of patients (methylated
group). Disease-free survival and overall survival at 9 years were 51
and 40%, respectively, for the unmethylated group and 3 and 2%,
respectively, for the methylated group (both P < 0.0001). Multivariate
analysis demonstrated that the Wnt methylation profile was an
independent prognostic factor predicting disease-free survival
(P = 0.007) and overall survival (P = 0.039). Abnormal DNA methylation
of promoter-associated CpG islands in the Wnt signaling pathway is
very common in Philadelphia chromosome-positive acute lymphoblastic
leukemia and potentially defines subgroups with distinct
clinical characteristics
Epigenetic regulation of PRAME gene in chronic myeloid leukemia
Tumor associated antigens (TAA) provide attractive targets for cancer-specific immunotherapy. PRAME is a TAA gene up-regulated in
advanced phases of chronic myeloid leukemia (CML). To date, molecular mechanisms for the expression of PRAME have never been studied.
We found that some Ph’-positive cell lines did not express PRAME. The expression of PRAMEwas restored in these cell lines by treatment with
5 -aza-2 -deoxycytidine, suggesting that the expression of PRAME is mainly suppressed by hypermethylation. Bisulfite sequencing analysis
of the CpG sites of the PRAME exon 2 in these cancer cell lines revealed a close relationship between the methylation status of the PRAME
gene and its expression. A methylation-specific PCR analysis demonstrated that hypomethylation of PRAME was significantly more frequent
in CML blast crisis (70%) than in chronic phase (36%) (P = 0.01) and was correlated with high expression levels of PRAME transcripts
(P < 0.0001). These results suggest that hypomethylation of PRAME up-regulates its expression in CML and might play a significant role in
the progression of the disease
Repetitive DNA hypomethylation in the advanced phase of chronic myeloid leukemia
Repetitive elements are heavily methylated in normal tissues, but hypomethylated in malignant tissues, driving the global genomic
hypomethylation found in cancer. This hypomethylation results in chromosomal instability, a well-characterized feature of the advanced
phases of chronic myeloid leukemia (CML). We investigated methylation changes of DNA repetitive elements (LINE1, Alu, Satellite-alpha
and Satellite-2) during the progression of CML from chronic phase (CP) to blast crisis (BC). CP-CML samples were significantly more
hypomethylated for all repetitive sequences compared with normal samples. Furthermore, a more profound level of hypomethylation was
observed among BC samples compared with CP samples. Our data suggest that repetitive DNA hypomethylation are closely associated with
CML progression