A truncated isoform of the human beta chain common to the receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 with increased mRNA expression in some patients with acute leukemia.
We report here a naturally occurring isoform of the human beta chain common to the receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 (GMRbetaC) with a truncated intracytoplasmic tail caused by deletion of a 104-bp exon in the membrane-proximal region of the chain. This beta intracytoplasmic truncated chain (betaIT) has a predicted tail of 46 amino acids, instead of 432 for betaC, with 23 amino acids in common with betaC and then a new sequence of 23 amino acids. In primary myeloid cells, betaIT comprised approximately 20% of the total beta chain message, but was increased up to 90% of total in blast cells from a significant proportion of patients with acute leukemia. Specific anti-betaIT antibodies demonstrated its presence in primary myeloid cells and cell lines. Coexpression of betaIT converted low-affinity GMRalpha chains (KD 2.5 nmol/L) to higher-affinity alphabeta complexes (KD 200 pmol/L). These could bind JAK2 that was tyrosine-phosphorylated by stimulation with GM-CSF. betaIT did not support GM-CSF-induced proliferation when cotransfected with GMRalpha into CTLL-2 cells. Therefore, it may interfere with the signal-transducing properties of the betaC chain and play a role in the pathogenesis of leukemia.
Gale
R E
RE
Department of Haematology, University College London Medical School, London, UK.
Freeburn
R W
RW
Khwaja
A
A
Chopra
R
R
Linch
D C
DC
D000208:Acute Disease; D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053614:Janus Kinase 2; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics*; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics*; D016185:Receptors, Interleukin-3 / Q000737:chemistry / Q000235:genetics*; D053649:Receptors, Interleukin-5; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D018123:Receptors, Interleukin; D016185:Receptors, Interleukin-3; D053649:Receptors, Interleukin-5; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2