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Nat Commun. 2018 May 2;9(1):1770. doi: 10.1038/s41467-018-04180-1.

De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia.

Author information

1
Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden.
2
Division of Molecular Hematology, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden.
3
Department of Pathology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA.
4
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 223 63, Lund, Sweden.
5
Department of Oncology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA.
6
Department of Computational Biology, St. Jude Children´s Research Hospital, Memphis, TN, 38105, USA.
7
Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden.
8
Division of Oncology, Skane University Hospital, Lund University, 221 85, Lund, Sweden.
9
Department of Pathology, Skane University Hospital, Lund University, 221 85, Lund, Sweden.
10
Medical Structural Biology, Department of Experimental Medical Science, 221 84 Lund University, Lund, Sweden.
11
Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 221 84, Lund, Sweden. Anna.Hagstrom@med.lu.se.

Abstract

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 FLT3 ITD , FLT3 N676K , and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3 N676K 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 Kras G12D locus, consistent with a strong selective advantage of additional Kras G12D . 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.

PMID:
29720585
PMCID:
PMC5932012
DOI:
10.1038/s41467-018-04180-1
[Indexed for MEDLINE]
Free PMC Article

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