vasoactive-intestinal-peptide and Leukemia--Myeloid--Acute

The genetic and transcriptional signature of EVI1 (ecotropic viral integration site 1)-rearranged (EVI1-r) acute myeloid leukemias (AMLs) remains poorly defined. We performed RNA sequencing of 12 EVI1-r AMLs and compared the results with those of other AML subtypes (n = 139) and normal CD34(+) cells (n = 17). Results confirm high frequencies of RAS and other activated signaling mutations (10/12 AMLs) and identify new recurrent mutations in splicing factors (5/12 AMLs in SF3B1 and 2/12 AMLs in U2AF1), IKZF1 (3/12 AMLs), and TP53 (3/12 AMLs). Mutations in IKZF1, a gene located on chromosome 7, and monosomy 7 are mutually exclusive in this disease. Moreover IKZF1 expression is halved in monosomy 7 leukemias. EVI-r AMLs are also characterized by a unique transcriptional signature with high expression levels of MECOM, PREX2, VIP, MYCT1, and PAWR. Our results suggest that EVI1-r AMLs could be molecularly defined by specific transcriptomic anomalies and a hitherto unseen mutational pattern. Larger patient cohorts will better determine the frequency of these events.

Topics: Apoptosis Regulatory Proteins; Chromosomes, Human, Pair 7; DNA-Binding Proteins; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Guanine Nucleotide Exchange Factors; Humans; Ikaros Transcription Factor; Leukemia, Myeloid, Acute; MDS1 and EVI1 Complex Locus Protein; Mutation; Nuclear Proteins; Proto-Oncogenes; Signal Transduction; Transcription Factors; Transcriptome; Tumor Suppressor Protein p53; Vasoactive Intestinal Peptide

A 93-kDa tyrosine protein kinase (p93) identified previously as the gene product of the c-fes proto-oncogene, is highly expressed in HL-60 leukemia cells induced to differentiate to the granulocyte or monocyte phenotype. We have now studied the relationship of p93 to the differentiation process by using a dimethyl sulfoxide (DMSO)-resistant subline of HL-60 cells (HL-60/DMSO) or the parental cell line treated with peptide or protein substrates of p93. Treatment of HL-60/DMSO cells with DMSO induced neither differentiation nor the expression of p93; however, cotreatment with IFN-alpha and DMSO resulted in partial differentiation and the concomitant induction of p93 activity. Treatment of wild-type HL-60 cells by the coaddition of the p93 substrates poly(Glu,Tyr)1:1, poly(Glu,Tyr)4:1, poly(Glu,Ala,Tyr)6:3:1, angiotensin II or vasoactive intestinal peptide with DMSO or IFN-tau partially blocked differentiation and concurrently diminished the induction of p93 activity. The inhibitory concentrations of the p93 substrates were related to their Km values. These results indicate that there is an obligatory association between the expression of p93 and granulocyte/monocyte differentiation in this cell line.

Topics: Cell Differentiation; Cell Line; Dimethyl Sulfoxide; Drug Resistance; Humans; Interferon Type I; Isoenzymes; Kinetics; Leukemia, Myeloid, Acute; Molecular Weight; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogenes; Vasoactive Intestinal Peptide

VIP is a 28 amino acid peptide found in highest concentration in central and peripheral nervous tissue. This study measured VIP in pure populations of peripheral blood cells to determine the presence or absence of VIP in noninnervated tissues. Cell populations were purified by Ficoll-hypaque gradient centrifugation followed by dextran sedimentation or differential adherence to culture plates. Platelets were purified by differential centrifugation. VIP was isolated by acid-ethanol extraction and quantified by radioimmunoassay. A mean value of 1.1 +/- 0.6 ng of VIP per 10(8) cells was extracted from PMNs. This peptide appears to be a specific marker for PMNs, since it was not measurable in pure populations of lymphocytes, monocytes, erythrocytes, or platelets. Mononuclear cells obtained from five patients with AML and seven patients with CML contained measurable VIP, whereas mononuclear cells from nine of 10 patients with AMML and from five patients with ALL contained very low or unmeasurable levels of VIP. Thus, although the role of VIP in normal PMN function is unknown, measurement of VIP in leukemic cells may aid in the differential diagnosis of acute leukemias.

Topics: Animals; Chemical Phenomena; Chemistry; Gastrointestinal Hormones; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neutrophils; Rabbits; Swine; Vasoactive Intestinal Peptide