Polycythemia vera blood burst-forming units-erythroid are hypersensitive to interleukin-3.

Abstract

Because polycythemia vera (PV) is a clonal hematopoietic stem cell disease with a trilineage hyperplasia, and interleukin-3 (I]L3) stimulates trilineage hematopoiesis, we have studied the response of highly purified PV blood burst-forming unitserythroid (BFU-E) to recombinant human IL-3 (rIL-3). Whereas the growth of normal blood BFU-E in vitro rapidly declined by 40 and 60% after 24 and 48 h of incubation without 50 U/ml of rIL-3, the growth of PV BFU-E declined by only 10 and 30% under the same conditions, demonstrating a reduced dependence on rIL-3. A reduced dependence of PV BFU-E on recombinant human erythropoietin (rEP) was also present. Dose-response experiments showed a 117-fold increase in PV BFU-E sensitivity to rIL-3, and a 6.5-fold increase in sensitivity to rEP, compared to normal BFU-E, whereas blood BFU-E from patients with secondary polycythemia responded like normal BFU-E. Endogenous erythroid colony (EEC) formation, which is independent of the addition of rEP, was reduced by 50% after erythroid colony-forming cells were generated from PV BFU-E in vitro without rIL-3 for 3 d, whereas rEP-stimulated erythroid colonies were unaffected. These studies demonstrate a striking hypersensitivity of PV blood BFU-E to rIL-3, which may be the major factor in the pathogenesis of increased erythropoiesis without increased EP concentrations. (J. Clin.

The gene encoding hematopoietic cell phosphatase (SHP-1) is structurally and transcriptionally intact in polycythemia vera

“…Puri®ed erythroid progenitors and de®ned serum-free culture conditions have been used to show that erythroid progenitors are hypersensitive to several dierent growth factors (Dai et al, 1992(Dai et al, , 1994Correa et al, 1994;Dudley et al, 1990). Furthermore, granulocyte/monocyte and megakaryocyte progenitors also displayed hypersensitivity to some growth factors (Dai et al, 1992;Kobayashi et al, 1993), a ®nding which accords well with the raised white blood cell and platelet counts often seen in patients with PV. Taken together, these observations suggest that the target gene(s) in PV may lie in a signal transduction pathway that is common to multiple dierent growth factors.…”

Complex oncogene dependence in microRNA-125a–induced myeloproliferative neoplasms

“…Hematopoietic cells from MPN patients often display hypersensitivity toward cytokines (15)(16)(17). To search for miRNAs that regulate cytokine sensitivity, we designed a barcode-based functional genomics screen in BaF3 cells, which strictly depends on IL-3 for survival and proliferation (18) (Fig.…”

Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

“…33 This hypersensitivity is selective to GM-CSF, with normal sensitivity in JMML precursors to interleukin-3 and to G-CSF, and therefore is unique in JMML, in that other myeloproliferative diseases can demonstrate cytokine hypersensitivity but usually this is to multiple cytokines. [34][35][36][37] Although much of JMML pathology revolves around the monocytic lineage, the pathogenesis of JMML has clearly been traced back to the stem cell level, and JMML is a clonal malignancy originating at the pluripotent stem cell level. 38,39 At the molecular pathogenetic level a clinical association between JMML and the dominant familial cancer syndrome neurofibromatosis type 1 led astute investigators to the Ras signaling pathway.…”