دورية أكاديمية
In vivo Targeting MEK and TNK2/SRC pathways in PTPN11 driven leukemia.
| العنوان: | In vivo Targeting MEK and TNK2/SRC pathways in PTPN11 driven leukemia. |
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| المؤلفون: | Chang BH, Thiel-Klare K, Tyner JW |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 17. Date of Electronic Publication: 2024 Jun 17. |
| نوع المنشور: | Journal Article; Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | PTPN11 encodes for a tyrosine phosphatase implicated in the pathogenesis of hematologic malignancies such as Juvenile Myelomonocytic Leukemia (JMML), Acute Myeloid Leukemia (AML), and Acute Lymphoblastic Leukemia (ALL). Since activating mutations of PTPN11 increase proliferative signaling and cell survival through the RAS/MAPK proliferative pathway there is significant interest in using MEK inhibitors for clinical benefit. Yet, single agent clinical activity has been minimal. Previously, we showed that PTPN11 is further activated by upstream tyrosine kinases TNK2/SRC, and that PTPN11-mutant JMML and AML cells are sensitive to TNK2 inhibition using dasatinib. In order to validate these findings, we adopted a genetically engineered mouse model of PTPN11 driven leukemia using the mouse strain 129S/Sv- Ptpn11 tm6Bgn /Mmucd crossed with B6.129P2- Lyz2 tm1(cre)Ifo /J. The F1 progeny expressing Ptpn11 D61Y within hematopoietic cells destined along the granulocyte-monocyte progenitor lineage developed a fatal myeloproliferative disorder characterized by neutrophilia and monocytosis, and infiltration of myeloid cells into the liver and spleen. Cohorts of Ptpn11 D61Y expressing animals treated with combination of dasatinib and trametinib for an extended period of time was well tolerated and had a significant effect in mitigating disease parameters compared to single agents. Finally, a primary patient-derived xenograft model using a myeloid leukemia with PTPN11 F71L also displayed improved disease response to combination. Collectively, these studies point to combined therapies targeting MEK and TNK2/SRC as a promising therapeutic potential for PTPN11-mutant leukemias. Key Points: Combining MEK and TNK2/SRC inhibitors has therapeutic potential in PTPN11 mutant JMML and AML. |
| تواريخ الأحداث: | Date Created: 20240527 Latest Revision: 20240625 |
| رمز التحديث: | 20240625 |
| مُعرف محوري في PubMed: | PMC11118393 |
| DOI: | 10.1101/2024.05.16.594555 |
| PMID: | 38798550 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2024.05.16.594555 |
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