title: 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 PTPN11G503A. To study the impact of PTPN11G503Acooperating with MLL/AF10 on leukemogenesis, we established a retroviral transduction/transplantation mouse model. Compared to the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11wt, the cells harboring PTPN11G503Awere hypersensitive to GM-CSF and IL3, and more resistant to death upon treatment with daunorubicin but sensitive to cytarabine. The cells harboring PTPN11G503Aautonomously 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 PTPN11G503Ahad a higher concentration of M-CSF in plasma. When mixed with the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11wt, the cells harboring PTPN11G503Ahad 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 PTPN11wtdeveloped myelomonocytic leukemia, while those transplanted with the cells harboring PTPN11G503A-induced monocytic leukemia in a shorter latency. Our results demonstrated that addition of PTPN11G503Ato MLL/AF10 affected cell proliferation, chemo-resistance, differentiation, in vivo BM recruitment/clonal expansion and accelerated disease progression.
authors.affiliation: Department of Medical Research, Chang Gung Memorial Hospital, and Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jen-Fen
authors.initials: JF
authors.lastname: Fu
authors.affiliation: Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Sung-Tzu
authors.initials: ST
authors.lastname: Liang
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Ying-Jung
authors.initials: YJ
authors.lastname: Huang
authors.affiliation: Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Kung-Hao
authors.initials: KH
authors.lastname: Liang
authors.affiliation: Department of Nephrology, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan.
authors.forename: Tzung-Hai
authors.initials: TH
authors.lastname: Yen
authors.affiliation: Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Der-Cherng
authors.initials: DC
authors.lastname: Liang
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.|Department of Internal Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018920:Coculture Techniques; D003561:Cytarabine / Q000627:therapeutic use; D003630:Daunorubicin / Q000627:therapeutic use; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007223:Infant; D007377:Interleukin-3 / Q000494:pharmacology; D007948:Leukemia, Monocytic, Acute / Q000209:etiology* / Q000235:genetics; D015479:Leukemia, Myelomonocytic, Acute / Q000209:etiology* / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D017354:Point Mutation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000502:physiology; D011828:Radiation Chimera; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured / Q000637:transplantation
chemical_list: D007377:Interleukin-3; C470550:MLL-AF10 fusion protein, human; D015514:Oncogene Proteins, Fusion; D003561:Cytarabine; D051788:Myeloid-Lymphoid Leukemia Protein; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D003630:Daunorubicin
keywords: M-CSF; MLL/AF10; PTPN11; cooperating leukemogenesis; monocytic leukemia