Publicação
The role of MYH10 in IL-7R-driven B-cell Acute Lymphoblastic Leukemia
| Resumo: | Acute lymphoblastic leukemia (ALL) is the most frequent type of cancer in children. IL-7/IL-7R dependent signaling was shown to play a role in ALL development and maintenance both in vitro and in vivo. Moreover, around 1% of B-cell Acute Lymphoblastic Leukemia (B-ALL) cases display IL-7R gain-of-function mutations leading to constitutive, ligand-independent signaling. Our laboratory developed a conditional mutant IL-7R knock-in mouse model, where the mutation is integrated into the mouse endogenous Il7r gene flanked by LoxP sites. This mouse line was crossed with CD2-iCre mouse to achieve the conditional expression of mutated IL-7R from the common lymphoid progenitor stage onwards. Interestingly, transcriptomics and proteomics analysis of leukemic cells from CD2-iCre.IL 7R mutant mice showed upregulation of Myosin heavy chain 10 (Myh10). Myh10 is upregulated in multiple cancers and is involved in the invasion and migration mechanisms of tumor cells. Therefore, we hypothesized that Myh10 may be a key player in the development of mutant IL-7R B-ALL. We crossed our conditional mutant with floxed Myh10 mice. We followed time-to-leukemia development and characterized this mouse model immunophenotypically by flow cytometry. Our results indicate that Myh10 does not play a role in the initiation of IL-7R-driven leukemia and does not prevent leukemia progression. Moreover, we observed that Myh10 deletion does not affect the immunophenotypic characteristics of IL-7R-driven tumors. However, histopathology results showed that mice without Myh10 had lower leukemic organ infiltration. Interestingly, transplantation experiments showed that leukemia cells without Myh10 originate disease in recipient mice more slowly than leukemia cells with Myh10 expression, leading to longer survival of transplanted animals. This raises the possibility that Myh10 may be important for disease relapse. Overall, our observations demonstrate for the first time that Myh10 is involved in mutant IL-7R-driven B-ALL and may be a potential therapeutic target. |
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| Autores principais: | Araújo, Tatiana Vanessa Fernandes |
| Assunto: | Myh10 IL-7R LLA B SNC Teses de mestrado - 2022 |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Acute lymphoblastic leukemia (ALL) is the most frequent type of cancer in children. IL-7/IL-7R dependent signaling was shown to play a role in ALL development and maintenance both in vitro and in vivo. Moreover, around 1% of B-cell Acute Lymphoblastic Leukemia (B-ALL) cases display IL-7R gain-of-function mutations leading to constitutive, ligand-independent signaling. Our laboratory developed a conditional mutant IL-7R knock-in mouse model, where the mutation is integrated into the mouse endogenous Il7r gene flanked by LoxP sites. This mouse line was crossed with CD2-iCre mouse to achieve the conditional expression of mutated IL-7R from the common lymphoid progenitor stage onwards. Interestingly, transcriptomics and proteomics analysis of leukemic cells from CD2-iCre.IL 7R mutant mice showed upregulation of Myosin heavy chain 10 (Myh10). Myh10 is upregulated in multiple cancers and is involved in the invasion and migration mechanisms of tumor cells. Therefore, we hypothesized that Myh10 may be a key player in the development of mutant IL-7R B-ALL. We crossed our conditional mutant with floxed Myh10 mice. We followed time-to-leukemia development and characterized this mouse model immunophenotypically by flow cytometry. Our results indicate that Myh10 does not play a role in the initiation of IL-7R-driven leukemia and does not prevent leukemia progression. Moreover, we observed that Myh10 deletion does not affect the immunophenotypic characteristics of IL-7R-driven tumors. However, histopathology results showed that mice without Myh10 had lower leukemic organ infiltration. Interestingly, transplantation experiments showed that leukemia cells without Myh10 originate disease in recipient mice more slowly than leukemia cells with Myh10 expression, leading to longer survival of transplanted animals. This raises the possibility that Myh10 may be important for disease relapse. Overall, our observations demonstrate for the first time that Myh10 is involved in mutant IL-7R-driven B-ALL and may be a potential therapeutic target. |
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