β common receptor inactivation attenuates myeloproliferative disease in Nf1 mutant mice

Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis

“…36,37 GM-CSF signaling is also required for fully penetrant MPD in Nf1 Ϫ/Ϫ mice 38,39 and the GM-CSF analog, E21R, inhibits JMML cell proliferation in vitro, in a mouse xenograft model and transiently in a JMML patient. 1 We find that GMPs and CMPs, upon acute expression of Ptpn11 D61Y in vitro and in vivo, give rise to myeloid colonies in the absence of exogenous cytokines.…”

Deficiency of β Common Receptor Moderately Attenuates the Progression of Myeloproliferative Neoplasm in Nras/+ Mice

“…Therefore, it is not surprising that the MP compartment remains expanded in ; ␤c Ϫ/Ϫ (Fig. 4) and Nf1 Ϫ/Ϫ ; ␤c Ϫ/Ϫ mice and that deletion of ␤c does not abrogate CMML in these animals (26).…”

“…Four of six Gmcsf Ϫ/Ϫ mice transplanted with Nf1 Ϫ/Ϫ ; Gmcsf Ϫ/Ϫ fetal liver cells develop JMML-like phenotypes with prolonged latency (24), which is postulated to be due to the residual activity of pre-formed GM-CSF receptor in the absence of GM-CSF (25). Subsequently, a study using the Mx1-Cre transgene to inactivate a conditional Nf1 allele in ␤c Ϫ/Ϫ hematopoietic cells shows that the severity of JMML-like phenotypes is reduced but not abrogated, whereas mice transplanted with Nf1 Ϫ/Ϫ ; ␤c Ϫ/Ϫ stem cells do not develop significant JMML over 1 year (26). Therefore, it remains elusive how GM-CSF signaling impacts on JMML/ MP-CMML initiation and progression.…”

Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

“…5,9,14,19 The absence of GM-CSF receptor signaling prevents the development of MPN in recipient mice receiving hematopoietic stem cells doubly deficient for Nf1 and the GM-CSF receptor common β chain. 16 Similarly, in an Nras G12D/+ model of MPN, β common chain deficiency did not prevent initiation of disease, but reduced splenomegaly and spontaneous colony formation and prolonged survival. 20 GM-CSF receptor signaling promotes proliferation and differentiation by activating a variety of signal transduction pathways including Janus kinase 2 -signal transducer and activator of transcription 5 (Jak2-Stat5) and Ras.…”

“…15 Notably, transplantation of Nf1-null fetal liver cells or somatic deletion of Nf1 in the hematopoietic compartment results in progressive myeloid expansion. 9,10,16,17 Furthermore, induced pluripotent stem cells, generated from two patients with JMML, differentiated into myeloid cells with high proliferative capacity and enhanced basal ERK (a well-known mediator of RAS activation) and STAT5 activation. 18 Malignant cells from JMML patients and JMML mouse models display hypersensitivity to certain cytokines, in particular granulocyte-macrophage colony-stimulating factor (GM-CSF).…”