Cooperation Of Mll/Af10(Om-Lz) With Ptpn11 Activating Mutation Induced Monocytic Leukemia With A Shorter Latency In A Mouse Bone Marrow Transplantation Model

PTPN11 mutation, a RAS signaling pathway mutation, is associated with MLL translocations in acute leukemia. A girl with MLL/AF10 AML was found to carry PTPN11(G503A). To study the impact of PTPN11(G503A) cooperating with MLL/AF10 on leukemogenesis, we established a retroviral transduction/transplantation mouse model. Compared to the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11(wt), the cells harboring PTPN11(G503A) were hypersensitive to GM-CSF and IL3, and more resistant to death upon treatment with daunorubicin but sensitive to cytarabine. The cells harboring PTPN11(G503A) autonomously differentiated into macrophages (1.8%) in the medium containing IL3. Further studies showed that the cells had an elevated (similar to 2.9-fold) Csf1 transcription level and secreted more (similar to 4.5-fold) M-CSF to the medium which can stimulate monocyte/macrophage differentiation of BM cells. Mice transplanted with the cells harboring PTPN11(G503A) had a higher concentration of M-CSF in plasma. When mixed with the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11(wt), the cells harboring PTPN11(G503A) had an increased competitive engraftment and clonal expansion in the BM and spleen of recipient mice, although no competitive growth advantage was observed in the in vitro co-culturing assays. The mice transplanted with the MLL/AF10(OM-LZ) cells harboring PTPN11(wt) developed myelomonocytic leukemia, while those transplanted with the cells harboring PTPN11(G503A)-induced monocytic leukemia in a shorter latency. Our results demonstrated that addition of PTPN11(G503A) to MLL/AF10 affected cell proliferation, chemo-resistance, differentiation, in vivo BM recruitment/clonal expansion and accelerated disease progression.