Circulating thrombopoietin as an in vivo growth factor for blast cells in acute myeloid leukemia

Abstract

Thrombopoietin (TPO), the major growth factor for cells of the megakaryocytic lineage, is removed from circulation by binding to c-mpl receptors present on platelets and megakaryocytes. We studied patients with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) and used TPO-induced c-fos protein up-regulation as a marker of cmpl functionality and observed that cmpl-presenting blast cells were present in 62% (37 of 60) of patients with ALL but that c-mpl was nonfunctional in 0 of 28 patients and that they were present in 56% (22 of 39) of patients with AML and were functional in 43% (12 of 28). Adequate increases in serum TPO level in response to thrombocytopenia were seen in patients with ALL and with c-mpldeficient (c-mpl ؊) AML. In contrast, in patients with c-mpl-proficient (c-mpl ؉ ) AML, TPO levels were found to be inappropriately low but increased to expected values during induction chemotherapy as blasts disappeared. In vitro significant TPO-associated blast cell proliferation or decreased apoptosis was observed only in patients with c-mpl ؉ AML compared with ALL or c-mpl ؊ AML and was highly correlated with low in vivo TPO levels (P < .001). These data suggest that, in patients with AML, inadequate TPO levels are secondary to TPO clearing by functional c-mpl receptor myeloid blast cells and that TPO may serve as an in vivo myeloid leukemic growth factor in a significant number of patients. IntroductionThrombopoietin (TPO) serum levels are controlled by a regulatory loop consisting of TPO consumption by target cells, platelets, and megakaryocytes (MGKs) through TPO c-mpl receptor-mediated absorption. 1 Thus, serum TPO level correlates inversely with platelet count in patients with hypoplastic thrombocytopenia, including chemotherapy-induced thrombocytopenia, 2-4 aplastic anemia, 5-7 myelodysplastic syndromes (MDS), and congenital amegakaryocytosis, 8 whereas no correlation is observed in patients with hyperdestructive thrombocytopenia 5 ; c-mpl has been observed on the surfaces of myeloid and lymphoid human blast cancer cells. 9-14 TPO in vitro induces cell cycle activation in human acute myeloblastic leukemia (AML) blast cells, 9,10,12,13 protects these cells from programmed cell death, 13 and, in TPO nonresponding cells, is synergistic with other growth factors to support the growth of leukemic myeloid blast cells. 9,12 Until now, no study has evaluated the relationship between serum TPO levels and the presence of c-mpl functional receptor on leukemic blast cells. However, through the evaluation of endogenous TPO level in patients with MDS and refractory anemia, it was found that though TPO level correlates inversely with platelet count in patients with refractory anemia, such correlation was not observed in patients with refractory anemia with excess blasts. This suggested that regulatory pathways other than thrombocytopenia, such as blast-expressing c-mpl, might operate in MDS. 15 In this study, we evaluated at the time of diagnosis serum TPO levels and functional c-mpl blast ce...

Down for the count in acute myeloid leukemia

“…Given the models of TPO homeostasis described previously, severe thrombocytopenia should result in increased circulating TPO. However, consistent with prior studies, 6 The biology of TPO and MPL is complex, and TPO and its receptor MPL play pleiotropic and far more important roles in regulating hematopoiesis than simply triggering thrombopoiesis. TPO can both induce expansion of HSCs but also paradoxically maintain HSC quiescence, possibly by operating at different signaling levels.…”

“…As an alternative, blast eradication with induction chemotherapy serves as an effective method for increasing TPO levels in AML patients with MPL-expressing blasts. 6 Although it is unlikely that TPO scavenging by MPL is the only determinant of cytopenias in AML patients, the work by Rauch et al supports an intriguing and novel model to explain the impairment of normal hematopoiesis in patients with AML. By stealing TPO, high levels of MPL on AML blasts might leave AML patients down for the count.…”

“…7,8 However, gene-corrected cells may have a selective growth advantage over parental HSCs with defects, and gene therapy can be successful even when only a small fraction of the transplanted HSC has been transduced by the vector. 6 Therefore, this system may prove to be a valuable method of clinical gene therapy. Several questions must be addressed before translating the findings of this paper to clinical trials.…”

Revealing eltrombopags promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation

“…20,44 It is well known that c-Mpl is expressed not only by hematopoietic progenitors, but also by many malignant hematopoietic cell types, and different in vitro experiments demonstrated that thrombopoietin may sustain the growth of both leukemic cell lines and human leukemic cells. 45,46 The concern that thrombopoietin mimetics might favor leukemogenesis has been extensively debated. A rise in blast counts has been seen in patients with MDS receiving romiplostim, 47 and a recent retrospective study of a large series of ITP patients indicated an association between the administration of thrombopoietin mimetics and the development of AML.…”

A prototype nonpeptidyl, hydrazone class, thrombopoietin receptor agonist, SB-559457, is toxic to primary human myeloid leukemia cells

“…2,8,9 One of these, a nonpeptidyl, hydrazone class small molecule, named Eltrombopag (E; SB-497115), was recently approved by the Food and Drug Administration for use in adult chronic idiopathic thrombocytopenic purpura patients. 10,11 Because Mpl and/or Tpo is expressed by many malignant hematopoietic cell types, [12][13][14] concern that Mpl agonists might exacerbate a leukemia patient's disease is appropriate. We investigated this issue using primary human leukemia cells and a prototype nonpeptidyl, hydrazone class, Mpl agonist, SB-559457 (SB; Figure 1A) whose in vitro megakaryocytopoietic properties are virtually indistinguishable from rhTpo (5M SB ϭ 100 ng/mL; 2.8M rhTpo).…”