Details

Autor(en) / Beteiligte

• Welch, John S.
• Ley, Timothy J.
• Link, Daniel C.
• Miller, Christopher A.
• Larson, David E.
• Koboldt, Daniel C.
• Wartman, Lukas D.
• Lamprecht, Tamara L.
• Liu, Fulu
• Xia, Jun
• Kandoth, Cyriac
• Fulton, Robert S.
• McLellan, Michael D.
• Dooling, David J.
• Wallis, John W.
• Chen, Ken
• Harris, Christopher C.
• Schmidt, Heather K.
• Kalicki-Veizer, Joelle M.
• Lu, Charles
• Zhang, Qunyuan
• Lin, Ling
• O’Laughlin, Michelle D.
• McMichael, Joshua F.
• Delehaunty, Kim D.
• Fulton, Lucinda A.
• Magrini, Vincent J.
• McGrath, Sean D.
• Demeter, Ryan T.
• Vickery, Tammi L.
• Hundal, Jasreet
• Cook, Lisa L.
• Swift, Gary W.
• Reed, Jerry P.
• Alldredge, Patricia A.
• Wylie, Todd N.
• Walker, Jason R.
• Watson, Mark A.
• Heath, Sharon E.
• Shannon, William D.
• Varghese, Nobish
• Nagarajan, Rakesh
• Payton, Jacqueline E.
• Baty, Jack D.
• Kulkarni, Shashikant
• Klco, Jeffery M.
• Tomasson, Michael H.
• Westervelt, Peter
• Walter, Matthew J.
• Graubert, Timothy A.
• DiPersio, John F.
• Ding, Li
• Mardis, Elaine R.
• Wilson, Richard K.

Titel

The Origin and Evolution of Mutations in Acute Myeloid Leukemia

Ist Teil von

• Cell, 2012-07, Vol.150 (2), p.264-278

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse. [Display omitted] ► Normal HSPCs contain random background mutations that increase with aging ► AML genomes contain hundreds of mutations, but very few are recurrent ► Comparison of M1 and M3 AML genomes identifies initiating versus cooperating mutations ► Most AML mutations are probably background events in HSPCs, “captured” by cloning Comparison of the genomes of two groups of patients, each with a different form of AML, allows the resolution of potential driver and cooperating mutations in each disease and reveals that the genetic history of all AML cases is marked by random, benign mutations acquired by normal HSPCs as a function of age.