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 . To study the impact of PTPN11 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 , the cells harboring PTPN11 were hypersensitive to GM-CSF and IL3, and more resistant to death upon treatment with daunorubicin but sensitive to cytarabine. The cells harboring PTPN11 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 had a higher concentration of M-CSF in plasma. When mixed with the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11 , the cells harboring PTPN11 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 developed myelomonocytic leukemia, while those transplanted with the cells harboring PTPN11 -induced monocytic leukemia in a shorter latency. Our results demonstrated that addition of PTPN11 to MLL/AF10 affected cell proliferation, chemo-resistance, differentiation, in vivo BM recruitment/clonal expansion and accelerated disease progression.

Ets1 Plays a Critical Role in MLL/EB1-Mediated Leukemic Transformation in a Mouse Bone Marrow Transplantation Model

“…The relationship between cell ratio (ME2G-shEts1/ ME2G-shEts1+ ME2G-shV) and nucleotide peak height ratio (T/T + G) was used to generate the standard curve (Supplementary Figure 3 B ). In vivo competitive engraftment/clonal expansion assays were performed as described previously 23 . The mice were sacrificed at 2, 4, 6, 8, and 10 weeks after transplantation (3 mice for each time point).…”

Role of SHP2 in hematopoiesis and leukemogenesis

“…In AML, PTPN11 G503A mutation has been reported to co-occur with mixed lineage leukemia (MLL) translocation, MLL-AF10. In a mouse model co-expression of MLL-AF10 and PTPN11 G503A resulted in accelerated disease development as compared to MLL-AF10 alone [23**]. Increase in leukemia stem cell frequency along with rapid AML development is also seen when Ptpn11 E76K is co-expressed with MLL-AF9 fusion oncogene [24].…”

“…Increase in leukemia stem cell frequency along with rapid AML development is also seen when Ptpn11 E76K is co-expressed with MLL-AF9 fusion oncogene [24]. In presence of mutant PTPN11, the leukemic cells show increase in the transcription of colony stimulating factor 1 (Csf1) and secretion of macrophage colony stimulating factor (M-CSF) resulting in enhanced differentiation of HSCs into myeloid lineage cells [23**]. Although co-expression of MLL-AF9 with constitutively active SHP2 does not alter the expression of Meis1 or HoxA9 [24], it can reverse cytokine induced tyrosine phosphorylation of HoxA9 and HoxA10 leading to sustained expression of CDX4, a homeodomain transcription factor (Figure 2) [25].…”

“…Thus its sustained high expression would inhibit differentiation and contribute to more stem cell like phenotype of leukemic cells. AML cells co-expressing mutant Ptpn11 with MLL fusion oncogenes are also more resistant to Mcl-1 inhibitor and daunorubicin [23**,24]. These studies provide insights into how co-existence of PTPN11 mutations can alter disease progression and drug resistance.…”

The Impact of PI3‐kinase/RAS Pathway Cooperating Mutations in the Evolution of KMT2A‐rearranged Leukemia

“…Mutations in the PTB domain including PTPN11 S502T and PTPN11 G503A/R/L/E have been reported in a case study and exhibit higher phosphatase activity as well. 18 These mutants dephosphorylates yet unknown substrates that negatively affect RAS signaling. Analysis of matched diagnostic and relapsed samples showed that PTPN11 G60V were retained in pediatric ALL patient while PTPN11 E76Q were gained at relapse.…”