A genome-scale in vivo loss-of-function screen identifies Phf6 as a lineage-specific regulator of leukemia cell growth.
We performed a genome-scale shRNA screen for modulators of B-cell leukemia progression in vivo. Results from this work revealed dramatic distinctions between the relative effects of shRNAs on the growth of tumor cells in culture versus in their native microenvironment. Specifically, we identified many "context-specific" regulators of leukemia development. These included the gene encoding the zinc finger protein Phf6. While inactivating mutations in PHF6 are commonly observed in human myeloid and T-cell malignancies, we found that Phf6 suppression in B-cell malignancies impairs tumor progression. Thus, Phf6 is a "lineage-specific" cancer gene that plays opposing roles in developmentally distinct hematopoietic malignancies.
The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Corbin E
CE
Meacham
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA;
Lee N
LN
Lawton
The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Yadira M
YM
Soto-Feliciano
The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Justin R
JR
Pritchard
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Brian A
BA
Joughin
The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Tobias
T
Ehrenberger
The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Nina
N
Fenouille
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
Johannes
J
Zuber
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Richard T
RT
Williams
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA;
Richard A
RA
Young
The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; hemann@mit.edu.
Michael T
MT
Hemann
D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D019070:Cell Lineage; D049109:Cell Proliferation / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins
D002352:Carrier Proteins; C502542:PHF6 protein, human; D034741:RNA, Small Interfering; D012097:Repressor Proteins
Phf6; context dependency; in vivo screen; leukemia