[Functional lateralization of major Chinese language cortex for presurgical evaluation in neurosurgery].

Objective: To investigate the functional lateralization of major Chinese language cortex in patients with cerebral arteriovenous malformation (AVM) in dominant hemispheric via functional magnetic resonance imaging (fMRI). Methods: Nine right-handed normal volunteers and fourteen patients with cerebral AVM in dominant hemisphere diagnosed in Beijing Tiantan Hospital between December 2017 and June 2018 were included. Three language tasks (semantic judgment, word reading, and listening comprehension) were applied to activate language areas. Lateralization index (LI) was used to show the dominant hemisphere. Results: In the control group, right-sided lateralization of BOLD signal activations was observed in 0/27 (0%) of the language tasks. While in the AVM patients, right-sided lateralization of BOLD signal activations was observed in 8/42 (19%) language tasks. The difference was statistically significant (χ(2)=5.73, P=0.019). Conclusions: The dominant hemisphere of different language tasks may be different in patients with cerebral lesions. Compared with normal controls, patients with cerebral AVM in dominant hemispheric are more likely to have right-sided lateralization of language cortex.

[Safety analysis of carotid endarterectomy without shunting in carotid artery stenosis patients with contralateral carotid occlusion].

Objective: To investigate the safety of carotid endarterectomy (CEA) without shunting in carotid artery stenosis (CAS) patients with contralateral carotid occlusion (CAO) under the protection of monitoring of cerebral blood oxygen saturation. Methods: A total of 71 patients with CAS was enrolled in our research during 2013 to 2016. They were divided into two groups which were group A: 20 CAS patients with contralateral CAO, and group B: 51 CAS patients without contralateral CAO. All patients were given CEA without shunting during operation.One and 6 months following up was carried to observe the incidence of newly hemorrhage and infarction on operation side and adverse cardiac events. Results: There was none adverse cardiac event and newly infarction. But there was 1 (5.00%) newly hemorrhage in group A during the 1 month following up. None adverse event was found in group B. During the 3 months following up, none adverse event was found in group A and 3 (5.88%) newly infarction patients were found in group B. However, there was no significant difference between group A and group B. Conclusion: CEA without shunting in CAS patients with contralateral carotid occlusion under the protection of monitoring of cerebral blood oxygen saturation is an efficient and safe way to improve the patients, living quality.

The elongation domain of ELL is dispensable but its ELL-associated factor 1 interaction domain is essential for MLL-ELL-induced leukemogenesis.

The MLL-ELL chimeric gene is the product of the (11;19)(q23p13.1) translocation associated with de novo and therapy-related acute myeloid leukemias (AML). ELL is an RNA polymerase II elongation factor that interacts with the recently identified EAF1 (ELL associated factor 1) protein. EAF1 contains a limited region of homology with the transcriptional activation domains of three other genes fused to MLL in leukemias, AF4, LAF4, and AF5q31. Using an in vitro transformation assay of retrovirally transduced myeloid progenitors, we conducted a structure-function analysis of MLL-ELL. Whereas the elongation domain of ELL was dispensable, the EAF1 interaction domain of ELL was critical to the immortalizing properties of MLL-ELL in vitro. To confirm these results in vivo, we transplanted mice with bone marrow transduced with MLL fused to the minimal EAF1 interaction domain of ELL. These mice all developed AML, with a longer latency than mice transplanted with the wild-type MLL-ELL fusion. Based on these results, we generated a heterologous MLL-EAF1 fusion gene and analyzed its transforming potential. Strikingly, we found that MLL-EAF1 immortalized myeloid progenitors in the same manner as that of MLL-ELL. Furthermore, transplantation of bone marrow transduced with MLL-EAF1 induced AML with a shorter latency than mice transplanted with the MLL-ELL fusion. Taken together, these results indicate that the leukemic activity of MLL-ELL requires the EAF1 interaction domain of ELL, suggesting that the recruitment by MLL of a transactivation domain similar to that in EAF1 or the AF4/LAF4/AF5q31 family may be a critical common feature of multiple 11q23 translocations. In addition, these studies support a critical role for MLL partner genes and their protein-protein interactions in 11q23 leukemogenesis.

Regulation of MEIS1 by distal enhancer elements in acute leukemia.

Aberrant activation of the three-amino-acid-loop extension homeobox gene MEIS1 shortens the latency and accelerates the onset and progression of acute leukemia, yet the molecular mechanism underlying persistent activation of the MEIS1 gene in leukemia remains poorly understood. Here we used a combined comparative genomics analysis and an in vivo transgenic zebrafish assay to identify six regulatory DNA elements that are able to direct green fluorescent protein expression in a spatiotemporal manner during zebrafish embryonic hematopoiesis. Analysis of chromatin characteristics and regulatory signatures suggests that many of these predicted elements are potential enhancers in mammalian hematopoiesis. Strikingly, one of the enhancer elements (E9) is a frequent integration site in retroviral-induced mouse acute leukemia. The genomic region corresponding to enhancer E9 is differentially marked by H3K4 monomethylation and H3K27 acetylation, hallmarks of active enhancers, in multiple leukemia cell lines. Decreased enrichment of these histone marks is associated with downregulation of MEIS1 expression during hematopoietic differentiation. Further, MEIS1/HOXA9 transactivate this enhancer via a conserved binding motif in vitro, and participate in an autoregulatory loop that modulates MEIS1 expression in vivo. Our results suggest that an intronic enhancer regulates the expression of MEIS1 in hematopoiesis and contributes to its aberrant expression in acute leukemia.

Retrovirus-mediated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice.

The MLL-ELL fusion gene results from the translocation t(11;19)(q23;p13.1) that is associated with de novo and therapy-related acute myeloid leukemia. To study its transforming properties, we retrovirally transduced primary murine hematopoietic progenitors and assessed their growth properties both in vitro and in vivo. MLL-ELL increased the proliferation of myeloid colony-forming cells in methylcellulose cultures upon serial replating, whereas overexpression of ELL alone had no effect. We reconstituted lethally irradiated congenic mice with bone marrow progenitors transduced with MLL-ELL or the control MIE vector encoding the enhanced green fluorescent protein. When the peripheral blood of the mice was analyzed 11-13 weeks postreconstitution, we found that the engraftment of the MLL-ELL-transduced cells was superior to that of the MIE controls. At this time point, the contribution of the donor cells was normally distributed among the myeloid and nonmyeloid compartments. Although all of the MIE animals (n = 10) remained healthy for more than a year, all of the MLL-ELL mice (n = 20) succumbed to monoclonal or pauciclonal acute myeloid leukemias within 100-200 days. The leukemic cells were readily transplantable to secondary recipients and could be established as immortalized cell lines in liquid cultures. These studies demonstrate the enhancing effect of MLL-ELL on the proliferative potential of myeloid progenitors as well as its causal role in the genesis of acute myeloid leukemias.

EAF1, a novel ELL-associated factor that is delocalized by expression of the MLL-ELL fusion protein.

The (11;19)(q23;p13.1) translocation in acute leukemia leads to the generation of a chimeric protein that fuses MLL to the transcriptional elongation factor ELL. A novel protein was isolated from a yeast 2-hybrid screen with ELL that was named EAF1 for ELL-associated factor 1. Using specific antibodies, the endogenous EAF1 and ELL proteins were coimmunoprecipitated from multiple cell lines. In addition, endogenous EAF1 also exhibited the capacity to interact with ELL2. Database comparisons with EAF1 identified a region with a high content of serine, aspartic acid, and glutamic acid residues that exhibited homology with the transcriptional activation domains of several translocation partner proteins of MLL, including AF4, LAF4, and AF5q31. A similar transcriptional activation domain has been identified in this region of EAF1. By confocal microscopy, endogenous EAF1 and ELL colocalized in a distinct nuclear speckled pattern. Transfection of the MLL-ELL fusion gene delocalized EAF1 from its nuclear speckled distribution to a diffuse nucleoplasmic pattern. In leukemic cell lines derived from mice transplanted with MLL-ELL-transduced bone marrow, EAF1 speckles were not detected. Taken together, these data suggest that expression of the MLL-ELL fusion protein may have a dominant effect on the normal protein-protein interactions of ELL.