Homeobox gene expression in acute myeloid leukemia is linked to typical underlying molecular aberrations

__Background:__ Although distinct patterns of homeobox (HOX) gene expression have been described in defined cytogenetic and molecular subsets of patients with acute myeloid leukemia (AML), it is unknown whether these patterns are the direct result of transcriptional alterations or rather represent the differentiation stage of the leukemic cell. __Method:__ To address this question, we used qPCR to analyze mRNA expression of HOXA and HOXB genes in bone marrow (BM) samples of 46 patients with AML and sorted subpopulations of healthy BM cells. These various stages of myeloid differentiation represent matched counterparts of morphological subgroups of AML. To further study the transcriptional alterations of HOX genes in hematopoiesis, we also analyzed gene expression of epigenetic modifiers in the subpopluations of healthy BM and leukemic cells. __Results:__ Unsupervised hierarchical clustering divided the AMLs into five clusters characterized by the presence of prevalent molecular genetic aberrations. Notably, the impact of genotype on HOX gene expression was significantly more pronounced than that of the differentiation stage of the blasts. This driving role of molecular aberrations was best exemplified by the repressive effect of the PML-RARa fusion gene on HOX gene expression, regardless of the presence of the FLT3/ITD mutation. Furthermore, HOX gene expression was positively correlated with mRNA levels of histone demethylases (JMJD3 and UTX) and negatively correlated with gene expression of DNA methyltranferases. No such relationships were observed in subpopulations of healthy BM cells. __Conclusion:__ Our results demonstrate that specific molecular genetic aberrations, rather than differentiation per se, underlie the observed differences in HOX gene expression in AML. Moreover, the observed correlations between epigenetic modifiers and HOX ex pression that are specific to malignant hematopoiesis, suggest their potential causal relationships

Chromosomal location of human genes encoding major heat-shock protein HSP70

The HSP70 family of heat-shock proteins constitutes the major proteins synthesized in response to elevated temperatures and other forms of stress. In eukaryotes members of the HSP70 family also include a protein similar if not identical to bovine brain uncoating ATPase and glucose-regulated proteins. An intriguing relation has been established between expression of heat-shock proteins and transformation in mammalian cells. Elevated levels of HSP70 are found in some transformed cell lines, and viral and cellular gene products that are capable of transforming cells in vitro can also stimulate transcription of HSP70 genes. To determine the organization of this complex multigene family in the human genome, we used complementary approaches: Southern analysis and protein gels of Chinese hamster-human somatic cell hybrids, and in situ hybridization to human chromosomes. We demonstrate that functional genes encoding HSP70 proteins map to human chromosomes 6, 14, 21, and at least one other chromosome .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45535/1/11188_2005_Article_BF01534692.pd

The ETS genes on chromosome 21 are distal to the breakpoint of the acute myelogenous leukemia translocation (8;21)

The definition of the genetic linkage map of human chromosomes may be helpful in the analysis of cancer-specific chromosome abnormalities. In the translocation (8;21)(q22;q22), a nonrandom cytogenetic abnormality of acute myelogenous leukemia (AML), we previously observed the transposition of the ETS2 gene located at the 21q22 region from chromosome 21 to chromosome 8. However, no ETS2 rearrangements were detected in the DNA of t(8;21)-positive AML cells. Genetic linkage analysis has allowed us to locate the ETS2 gene relative to other loci and to establish that the breakpoint is at an approximate genetic distance of 17 cM from ETS2. When the information from the linkage map is combined with that from molecular studies, it is apparent that (a) the t(8;21) breakpoint does not affect the ETS2 gene structure or the structure of the other four loci proximal to ETS2: D21S55, D21S57, D21S17, and ERG, and ETS-related gene; and (b) the actual DNA sequence involved in the t(8;21) must reside in a 3-cM genetic region between the D21S58 and the D21S55/D21S57 loci, and remains to be identified