Cooperation of MLL/AF10(OM-LZ) with PTPN11 activating mutation induced monocytic leukemia with a shorter latency in a mouse bone marrow transplantation model

Abstract

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 (∼2.9-fold) Csf1 transcription level and secreted more (∼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.

Keywords: M-CSF; MLL/AF10; PTPN11; cooperating leukemogenesis; monocytic leukemia.