Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition
| Autor: | Lili Chen, Andrew G. Muntean, Wei Chen, Maria Mysliwski, Ari Melnick, Ross L. Levine, James Ropa, Justin Serio, Zaneta Nikolovska-Coleska, Rebecca J. Chan, Jay P. Patel, Fardokht A. Abulwerdi, Martin S. Tallman, Omar Abdel-Wahab, Elisabeth Paietta |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Myeloid Oncogene Proteins Fusion Blotting Western Apoptosis Protein Tyrosine Phosphatase Non-Receptor Type 11 Biology Real-Time Polymerase Chain Reaction Article 03 medical and health sciences Mice 0302 clinical medicine Cancer stem cell hemic and lymphatic diseases medicine Tumor Cells Cultured Animals Humans MCL1 RNA Messenger RNA Small Interfering neoplasms 030304 developmental biology Cell Proliferation 0303 health sciences Juvenile myelomonocytic leukemia Reverse Transcriptase Polymerase Chain Reaction Myeloid leukemia Hematology medicine.disease 3. Good health Mice Inbred C57BL Leukemia Haematopoiesis Leukemia Myeloid Acute medicine.anatomical_structure Oncology Clinical Trials Phase III as Topic Drug Resistance Neoplasm 030220 oncology & carcinogenesis Immunology Mutation Cancer research Neoplastic Stem Cells Myeloid Cell Leukemia Sequence 1 Protein Female Interleukin-3 Stem cell Apoptosis Regulatory Proteins |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 data set. We examined the role of mutated Shp2 in leukemias harboring MLL translocations, which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9-mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. Although the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K, suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small-molecule-mediated Mcl1 inhibition, suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2. |
| Databáze: | OpenAIRE |
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