An Alternative Transcript of the Human GM-CSF Receptor Alpha Chain Lacking the Signal Sequence Is Found in AML Blasts and Normal Controls

Abstract

Blast cells from 70% of patients with acute myeloid leukaemia (AML) show autonomous growth characteristics. One of the autocrine growth factors involved is granulocytemacrophage colony-stimulating factor (GMCSF). The receptor for GM-CSF (GM-CSFR) is composed of at least 2 chains. The alpha chain binds GM-CSF specifically but with low affinity. The beta chain confers high affinity binding when associated with the alpha chain. So far at least 6 alternative transcripts of the alpha chain have been described which differ from each other in the 3′ end of the coding sequence. Using RT-PCR of RNA from normal bone marrow mononuclear cells and blast cells from patients with AML we have found an mRNA transcript with a deletion of 102 nucleotides (nt) between nt 123 and 226 of the published sequence. This deletion removes the original initiation codon and the signal peptide sequence. Translation would still be possible starting from ATG (nt 282-284), creating an alpha chain lacking the signal peptide and the first 22 amino acids of the extracellular protein sequence. In RNAse protection assays transcripts carrying the 102 nt deletion were expressed at levels of about 20% of the total alpha chain message in normal bone marrow cells. In blasts from AML patients expression varied between 5 and 60%. Full length GM-CSFR alpha RT-PCR products from a patient with AML showed that transcripts carrying the 102 nt deletion also lack the sequence coding for the transmembrane domain. Translation of this mRNA transcript would therefore produce a signal peptide deficient, soluble GM-CSFR alpha isoform that might be confined to the cytosol. It is possible that such a cytosolic receptor chain could be involved in intracellular autocrine loops.