Expression and functionality of the trkA proto-oncogene product/NGF receptor in undifferentiated hematopoietic cells

Abstract

The expression of the low-affinity NGF receptor (p75) and the trkA proto-oncogene product was analyzed in a series of human hematopoietic cell lines at protein and RNA levels. We did not detect any form of NGF receptor in cell lines displaying a myelomonocytic phenotype (HL60 and U937). In contrast, cells displaying a more immature erythroleukemic phenotype (TF1 and K562) expressed TrkA in the absence of detectable p75. Scatchard analysis showed a single high-affinity site for NGF (kd = 10(-10) mol/L), with a copy number ranging from 300 to 3,000 sites per cell depending on the studied cell line. In addition, NGF induced autophosphorylation of TrkA and could substitute for granulocyte- monocyte colony-stimulating factor to trigger the proliferation of the TF1 cell line, with a half-maximal signal observed at 50 pmol/L, indicating that p75 is not required for DNA synthesis in this cell line. The physiologic relevance of NGF in early hematopoiesis was confirmed by showing that 12% to 15% of progenitor blood cells from mice treated with 5-fluorouracil expressed TrkA and that these cells could be induced to proliferate and differentiate in response to NGF in association with macrophage colony-stimulating factor. Our study demonstrates for the first time that trkA proto-oncogene expression and activation is not restricted to the nervous system, but is also an important element in early hematopoiesis.

Expression of mRNA encoding neurotrophins and neurotrophin receptors in human granulocytes and bone marrow cells—enhanced neurotrophin-4 expression induced by LTB4

“…Expression of trkA protein has previously been reported only in mouse bone marrow [19]. In the present study we report for the first time expression of mRNA coding for trkA in normal human bone marrow.…”

“…Further studies on this issue are warranted. NGF has been suggested to be involved in early hematopoiesis [19]. Similarly, LTB 4 and LTC 4 , which are readily produced by human bone marrow [51,52], can stimulate GM-CSFinduced normal myelopoiesis in vitro [45].…”

“…Thus, mRNAs for NGF, NT-3, NT-4 [13,14], as well as trkA [14,15] were identified in rodent lymphocytes, while rodent mast cells were reported to produce NGF [16]. In the human, trkA mRNA was expressed in monocytes [17], basophils [18], and undifferentiated hematopoietic cell lines [19]. Furthermore, functional studies have demonstrated that NGF, the rkA ligand, can modulate the prolifera-tion and differentiation of B [20][21][22][23] and T [24,25] lymphocytes and may operate as an autocrine survival factor for memory B lymphocytes [26].…”

Expression of the nerve growth factor receptor c‐TRK in human myeloid leukaemia cells

“…In that report, TRK expression was described to decrease during the in vitro differentiation from monocytes to macrophages, suggesting a maturation-dependent TRK regulation. In a recent publication (Chevalier et al, 1994), TRK-A expression was detected in K562 cells and in the growth factor-dependent cell line TF-1. TRK-A expression was associated with a more immature phenotype in the cell lines examined.…”

Expression of the p75 neurotrophin receptor in acute leukaemia

“…poiesis (Chevalier et al, 1994;Torcia et al, 1996), such as survival of memory B cells (Torcia et al, 1996). Deregulated expression or mutation of NT receptors may be involved in the initiation and progression of human cancers (McGregor et al, 1999;Descamps et al, 2001).…”