Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells.

This corrects the article DOI: 10.1038/leu.2014.119.

Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells.

The histone demethylase LSD1 (KDM1A) demethylates mono- and di-methylated (Me2) lysine (K) 4 on histone H3. High LSD1 expression blocks differentiation and confers a poor prognosis in acute myeloid leukemia (AML). Here, treatment with the novel LSD1 antagonist SP2509 attenuated the binding of LSD1 with the corepressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters, and increased the levels of p21, p27 and CCAAT/enhancer binding protein α in cultured AML cells. In addition, SP2509 treatment or LSD1 shRNA inhibited the colony growth of AML cells. SP2509 also induced morphological features of differentiation in the cultured and primary AML blasts. SP2509 induced more apoptosis of AML cells expressing mutant NPM1 than mixed-lineage leukemia fusion oncoproteins. Treatment with SP2509 alone significantly improved the survival of immune-depleted mice following tail-vein infusion and engraftment of cultured or primary human AML cells. Co-treatment with pan-HDAC inhibitor (HDI) panobinostat (PS) and SP2509 was synergistically lethal against cultured and primary AML blasts. Compared with each agent alone, co-treatment with SP2509 and PS significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Collectively, these findings show that the combination of LSD1 antagonist and pan-HDI is a promising therapy warranting further testing against AML.

A transcript map of the chromosome 19q-arm glioma tumor suppressor region.

Allelic loss of the chromosome 19q arm is a frequent event in human diffuse gliomas, suggesting that it contains a tumor suppressor gene. Recent deletion mapping studies have broadly implicated a 1.6-Mb interval between D19S241E and D19S596, with a limited subset of tumors, suggesting that the region may be as narrow as 150 kb. Focusing on this smaller interval, we have used cDNA selection, exon amplification, and genomic sequencing to identify three novel transcripts (EHD2, GLTSCR1, and GLTSCR2) and to map two known genes (SEPW1 and CRX). A partial transcript map of 19 transcripts and two EST markers has been constructed for the 1.6-Mb interval D19S241E-D19S596. Ten of these transcripts, including the 5 mapped to the 150-kb deletion interval, have been examined for alterations in a panel of gliomas with allelic loss of 19q. Tumor-specific alterations have not been identified in the transcripts examined thus far. Collectively, these data should facilitate subsequent efforts to identify and characterize the remaining transcripts in the 1.6-Mb interval.

The human glia maturation factor-gamma gene: genomic structure and mutation analysis in gliomas with chromosome 19q loss.

Human glia maturation factor-gamma (hGMF-gamma) is a recently identified gene that may be involved in glial differentiation, neural regeneration, and inhibition of tumor cell proliferation. The gene maps to the long arm of chromosome 19 at band q13.2, a region that is frequently deleted in human malignant gliomas and is thus suspected to harbor a glioma tumor suppressor gene. Given the putative role of hGMF-gamma in cell differentiation and proliferation and its localization to chromosome 19q13, this gene is an interesting candidate for the chromosome 19q glioma tumor suppressor gene. To evaluate this possibility, we determined the genomic structure of human hGMF-gamma and performed mutation screening in a series of 41 gliomas with and without allelic loss of chromosome 19q. Mutations were not detected, which suggests that hGMF-gamma is not the chromosome 19q glioma suppressor gene. However, the elucidation of the genomic structure of hGMF-gamma may prove useful in future investigations of hGMF-gamma in the normal adult and developing human nervous system.

Thermoregulatory response to wearing encapsulated protective clothing during simulated work in various thermal environments.

This investigation assessed the thermoregulatory impact of performing simulated tasks normally encountered during chemical accident clean-up while wearing chemical protection clothing under various representative thermal loads. A Drager 500 (D) suit was worn with a self-contained breathing apparatus (SCBA) external to the suit, while both a Trelleborg Trellchem Super Extra (T) and a James North MZ500 (J) suit required the SCBA to be worn inside the suit. The D suit was unventilated, while the T and S suits were ventilated with the subject's exhaled air. The T suit also was ventilated via a 2 L/min flow of air from the SCBA. Subjects were six firefighters. Each simulation lasted for 30 minutes and involved tasks such as drum rolling, drum carrying, walking, and hose dragging. The trials were conducted at 11.3, 17.1, and 23.8 degrees C WBGT. The overall mean peak heart rate was 128.1 +/- 2.80 breaths/min and was elicited while performing lifting tasks. Nonsignificant differences (p > 0.05) were observed for both the average heart rate and sweat rate. Mean skin temperature, mean body temperature, and temperature within the suit cavity were significantly higher when wearing the D suit compared to wearing T or J suits; differences between the T and J suits were nonsignificant. Suit type did not significantly affect rectal temperature, which also failed to exceed the American Council of Governmental Industrial Hygienists' (ACGIH) standard of 38.0 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)