(ClinicalTrials.gov number, NCT00391872.)”
“BACKGROUND
The full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known.
METHODS
We used massively parallel DNA sequencing to obtain a very high level of coverage (approximately 98%) find more of a primary, cytogenetically normal, de novo genome for AML with minimal maturation (AML-M1) and a matched normal skin genome.
RESULTS
We identified 12 acquired (somatic) mutations within
the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions of the genome. All mutations appeared to be heterozygous and present in nearly all cells in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were tested. Mutations in NRAS and NPM1 had been identified previously in patients
with AML, but two other mutations had not been identified. One of these mutations, in the IDH1 gene, was present in 15 of 187 additional AML genomes tested and was strongly associated with normal cytogenetic status; it was present Selleckchem MK-2206 in 13 of 80 cytogenetically normal samples (16%). The other was a nongenic mutation in a genomic region with regulatory potential and conservation in higher mammals; we detected it in one additional AML tumor. The AML genome that we sequenced contains approximately 750 point mutations, of which only a small fraction are likely to be relevant to pathogenesis.
CONCLUSIONS
By comparing the sequences of tumor and skin
genomes of a patient with AML-M1, we have identified recurring mutations that may be relevant for pathogenesis.”
“BACKGROUND
Progressive multifocal leukoencephalopathy (PML) occurs in a fraction of patients with multiple sclerosis who were treated with natalizumab. Most adults who are infected with the JC virus, the etiologic agent in PML, do not have symptoms. We sought to determine whether exposure to natalizumab causes subclinical reactivation and neurotropic transformation of JC virus.
METHODS
We followed 19 consecutive patients with multiple sclerosis who were treated with natalizumab over an 18-month period, performing quantitative polymerase-chainreaction assays in blood and urine for JC virus reactivation; BK virus, a JC virus-related polyomavirus, Caspase Inhibitor VI mw was used as a control. We determined JC virus-specific T-cell responses by means of an enzyme-linked immunospot assay and antibody responses by means of an enzyme-linked immunosorbent assay and analyzed JC virus regulatory-region sequences.
RESULTS
After 12 months of natalizumab therapy, the prevalence of JC virus in the urine of the 19 patients increased from a baseline value of 19% to 63% (P = 0.02). After 18 months of treatment, JC virus was detectable in 3 of 15 available plasma samples (20%) and in 9 of 15 available samples of peripheral-blood mononuclear cells (60%) (P = 0.02).