Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment

Abstract

Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway1, are found in 50% of patients with Noonan syndrome2. These patients have an increased risk of developing leukaemia3, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity4–7. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias.

AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth

“…In another report, Kousteni's group suggests that activating β-catenin mutations in osteoblasts induce AML in mice (29). Very recently, Dong and Yu et al, reported that Ptpn11 mutations in osteoprogenitor and mesenchymal stem cells induced myeloproliferative neoplasm but that the same mutations in endothelial cells or mature osteoblasts did not induce this effect on myeloid cell compartment (30). These reports from different labs suggest that osteogenic niches support leukemia growth and disease progression.…”

Sipa1 deficiency–induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm

“…2,11 However, the cellular and molecular mechanisms underlying the microenvironment-induced leukemogenesis remain poorly understood. We here demonstrate that Sipa1 deletion results in BM niche alterations leading to the development of MDS/MPN.…”

Neoplasms in the bone marrow niches: disturbance of the microecosystem

“…Several studies found that deletion or mutation of functional genes in these niche cells led to MPNs, myelodysplasia, or leukemia [12,[28][29][30][31][32]. These findings and accordingly raised concepts were proved by the clinical transplantation investigations, in which donor-derived hematologic malignancies after hematopoietic stem cell transplantation were diagnosed [33].…”