التفاصيل البيبلوغرافية
| العنوان: |
De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia. |
| المؤلفون: |
Hyrenius-Wittsten, Axel, Pilheden, Mattias, Sturesson, Helena, Hansson, Jenny, Walsh, Michael P., Guangchun Song, Kazi, Julhash U., Jian Liu, Ramakrishan, Ramprasad, Garcia-Ruiz, Cristian, Nance, Stephanie, Gupta, Pankaj, Zhang, Jinghui, Rönnstrand, Lars, Hultquist, Anne, Downing, James R., Lindkvist-Petersson, Karin, Paulsson, Kajsa, Järås, Marcus, Gruber, Tanja A. |
| المصدر: |
Nature Communications; 5/2/2018, Vol. 9 Issue 1, p1-13, 13p, 5 Graphs |
| مستخلص: |
Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3ITD, FLT3N676K, and NRASG12D accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3N676K mutations accelerate disease, possibly by providing stimulatory factors. Herein, we show that one such factor, MIF, promotes survival of mouse KMT2A-MLLT3 leukemia initiating cells. We identify acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 in KMT2A-MLLT3 leukemia cells that favored clonal expansion. During clonal evolution, we observe serial genetic changes at the KrasG12D locus, consistent with a strong selective advantage of additional KrasG12D. KMT2A-MLLT3 leukemias with signaling mutations enforce Myc and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlight the importance of activated signaling as a contributing driver. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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