Returning to life activities after hematopoietic cell transplantation in older adults.

OBJECTIVES: The prevalence of hematopoietic cell transplant (HCT) among older adults with hematological malignancies has more than doubled over the last decade and continues to grow. HCT is an intense process that can impact functional status and health-related quality of life. The objective of this paper is to describe the experience of returning to life activities after HCT in patients 60 years of age and older and the resources required to adapt and cope to limitations in physical, psychological, and cognitive function. MATERIALS AND METHODS: Twenty English speaking adults 60 years and older with hematological malignancy 3 to 12 months post-HCT completed semi-structured interviews. Open-ended questions and probes were guided by the Transactional Model of Stress and Coping to explore adaptive functioning, coping resources, and coping strategies. An integrated grounded theory approach was used to code the textual data to identify themes. The study took place at a tertiary comprehensive cancer center in the Midwest United States. RESULTS: Eight allogeneic and twelve autologous HCT recipients participated in the interviews. Nineteen participants were within 6-12 months and 1 participant was at 3 months post-HCT. Our findings identify the significant role of engaging in life activities and social support in the recovery of physical, psychological and cognitive function. CONCLUSION: Older HCT recipients are an understudied population. They are at high risk for functional decline. Our findings may provide community oncologists and primary care physicians with a context for providing care to older HCT survivors during their recovery.

HDAC1 Is a Required Cofactor of CBFß-SMMHC and a Potential Therapeutic Target in Inversion 16 Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a neoplastic disease characterized by the uncontrolled proliferation and accumulation of immature myeloid cells. A common mutation in AML is the inversion of chromosome 16 [inv (16)], which generates a fusion between the genes for core binding factor beta (CBFB) and smooth muscle myosin heavy chain gene (MYH11), forming the oncogene CBFB-MYH11. The expressed protein, CBFß-SMMHC, forms a heterodimer with the key hematopoietic transcription factor RUNX1. Although CBFß-SMMHC was previously thought to dominantly repress RUNX1, recent work suggests that CBFß-SMMHC functions together with RUNX1 to activate transcription of specific target genes. However, the mechanism of this activity or a requirement for additional cofactors is not known. Here, we show that the epigenetic regulator histone deacetylase 1 (HDAC1) forms a complex with CBFß-SMMHC, colocalizes with RUNX1 and CBFß-SMMHC on the promoters of known fusion protein target genes, and that Hdac1 is required for expression of these genes. These results imply that HDAC1 is an important component of the CBFß-SMMHC transcriptional complex, and that leukemia cells expressing the fusion protein may be sensitive to treatment with HDAC1 inhibitors. Using a knock-in mouse model expressing CBFß-SMMHC, we found that in vivo treatment with the HDAC1 inhibitor entinostat decreased leukemic burden, and induced differentiation and apoptosis of leukemia cells. Together, these results demonstrate that HDAC1 is an important cofactor of CBFß-SMMHC and a potential therapeutic target in inv (16) AML. IMPLICATIONS: This report describes a novel role for HDAC1 as a cofactor for the leukemogenic fusion protein CBFß-SMMHC and shows that inhibitors of HDAC1 effectively target leukemia cells expressing the fusion protein in vivo.

Genetic basis for a rare floral mutant in an Andean species of Solanaceae.

PREMISE OF THE STUDY: White forms of typically pigmented flowers are one of the most common polymorphisms in flowering plants. Although the range of genetic changes that give rise to white phenotypes is well known from model systems, few studies have identified causative mutations in natural populations. METHODS: Here we combine genetic studies, in vitro enzyme assays, and biochemical analyses to identify the mechanism underlying the loss of anthocyanin pigment production in the naturally occurring white-flowered morph of Iochroma calycinum (Solanaceae). KEY RESULTS: Comparison of anthocyanin gene sequences revealed a putative loss-of-function mutation, an 11 amino-acid deletion in dihydroflavonol 4-reductase (DFR), in the white morph. Functional assays of Dfr alleles from blue and white morphs demonstrated that this deletion results in a loss of enzymatic activity, indicating that the deletion could be solely responsible for the lack of pigment production. Consistent with this hypothesis, quantitative PCR showed no significant differences in expression of anthocyanin genes between the morphs. Also, thin layer chromatography confirmed that the white morph continues to accumulate compounds upstream of the DFR enzyme. CONCLUSIONS: Collectively, these experiments indicate that the structural mutation at Dfr underlies the rare white flower morph of I. calycinum. This study is one of only a few examples where a flower color polymorphism is due to a loss-of-function mutation in the coding region of an anthocyanin enzyme. The rarity of such mutations in nature suggests that negative consequences prevent fixation across populations.

The generation of chromosomal deletions to provide extensive coverage and subdivision of the Drosophila melanogaster genome.

BACKGROUND: Chromosomal deletions are used extensively in Drosophila melanogaster genetics research. Deletion mapping is the primary method used for fine-scale gene localization. Effective and efficient deletion mapping requires both extensive genomic coverage and a high density of molecularly defined breakpoints across the genome. RESULTS: A large-scale resource development project at the Bloomington Drosophila Stock Center has improved the choice of deletions beyond that provided by previous projects. FLP-mediated recombination between FRT-bearing transposon insertions was used to generate deletions, because it is efficient and provides single-nucleotide resolution in planning deletion screens. The 793 deletions generated pushed coverage of the euchromatic genome to 98.4%. Gaps in coverage contain haplolethal and haplosterile genes, but the sizes of these gaps were minimized by flanking these genes as closely as possible with deletions. In improving coverage, a complete inventory of haplolethal and haplosterile genes was generated and extensive information on other haploinsufficient genes was compiled. To aid mapping experiments, a subset of deletions was organized into a Deficiency Kit to provide maximal coverage efficiently. To improve the resolution of deletion mapping, screens were planned to distribute deletion breakpoints evenly across the genome. The median chromosomal interval between breakpoints now contains only nine genes and 377 intervals contain only single genes. CONCLUSIONS: Drosophila melanogaster now has the most extensive genomic deletion coverage and breakpoint subdivision as well as the most comprehensive inventory of haploinsufficient genes of any multicellular organism. The improved selection of chromosomal deletion strains will be useful to nearly all Drosophila researchers.