Identification of Basophils as a Major Source of Hepatocyte Growth Factor in Chronic Myeloid Leukemia: A Novel Mechanism of BCR-ABL1-Independent Disease Progression

Abstract

Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the Philadelphia chromosome and the related BCR-ABL1 oncoprotein. Acceleration of CML is usually accompanied by basophilia. Several proangiogenic molecules have been implicated in disease acceleration, including the hepatocyte growth factor (HGF). However, little is known so far about the cellular distribution and function of HGF in CML. We here report that HGF is expressed abundantly in purified CML basophils and in the basophil-committed CML line KU812, whereas all other cell types examined expressed only trace amounts of HGF or no HGF. Interleukin 3, a major regulator of human basophils, was found to promote HGF expression in CML basophils. By contrast, BCR-ABL1 failed to induce HGF synthesis in CML cells, and imatinib failed to inhibit expression of HGF in these cells. Recombinant HGF as well as basophil-derived HGF induced endothelial cell migration in a scratch wound assay, and these effects of HGF were reverted by an anti-HGF antibody as well as by pharmacologic c-Met inhibitors. In addition, anti-HGF and c-Met inhibitors were found to suppress the spontaneous growth of KU812 cells, suggesting autocrine growth regulation. Together, HGF is a BCR-ABL1-independent angiogenic and autocrine growth regulator in CML. Basophils are a unique source of HGF in these patients and may play a more active role in disease-associated angiogenesis and disease progression than has so far been assumed. Our data also suggest that HGF and c-Met are potential therapeutic targets in CML.

The underestimated role of basophils in Ph+ chronic myeloid leukaemia

“…55, 56, 57, 58 In particular, it has been described that patients with CML exhibit elevated HGF levels in their PB and BM and that expression of HGF in the BM correlates with the microvessel density in BM sections 55, 56, 57, 58. Moreover, increased PB levels of HGF correlate with the prognosis in CML 57, 58. Other studies have shown that HGF is specifically synthesized by CML basophils and that basophil‐derived HGF promotes migration and growth of endothelial cells through a specific receptor 58.…”

“…However, not all angiogenic and fibrogenic cytokines are produced in CML cells in a BCR‐ABL1‐dependent manner. For example, HGF is produced in CML basophils independent of BCR‐ABL1 58. In fact, the biochemical basis underlying expression and release of HGF in basophils in CML remains at present unknown.…”

“…First, as mentioned, basophils are a rich source of vascular growth factors and may thus be able to contribute to stem cell‐niche expansion and increased angiogenesis. Moreover, basophils display many vascular permeability‐augmenting substances, including VEGF (identical with vascular permeability factor, VPF), HGF and histamine 58, 59, 60, 61, 62. These molecules may well facilitate stem cell redistribution from the BM into the circulation and also from the PB into extramedullary organs (Figure 3).…”

“…Finally, basophils may produce and release autocrine growth regulators that act on neoplastic stem and progenitor cells in the CML clone (Figure 3). For example, it has been described that CML stem cells display c‐MET, the receptor for HGF and that basophil‐derived HGF acts as an autocrine growth regulator on CML LSC in the malignant clone 58. Indeed, HGF is a well‐known regulator of early myeloid progenitor cells 80, 81, 82…”

MIP-1α/CCL3-expressing basophil-lineage cells drive the leukemic hematopoiesis of chronic myeloid leukemia in mice

“…In addition, patients with CML frequently exhibit basophilia in the BM and peripheral blood (PB), which becomes more pronounced in the accelerated phase. 3,4 However, the pathogenic roles of basophil-like leukemia cells during disease progression are poorly understood because of a lack of information on the molecule(s) produced by these cells.…”