Abstract
Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL-CBP expression and to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/ macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal γ-irradiation or N-ethyl-N-nitrosourea (ENU), MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy-induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/ myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.
| Original language | English |
|---|---|
| Pages (from-to) | 368-381 |
| Number of pages | 14 |
| Journal | EMBO Journal |
| Volume | 24 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Jan 26 2005 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Neuroscience(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)
Cite this
Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. / Wang, Jing; Iwasaki, Hiromi; Krivtsov, Andrei; Febbo, Phillip G.; Thorner, Aaron R.; Ernst, Patricia; Anastasiadou, Erna; Kutok, Jeffery L.; Kogan, Scott C.; Zinkel, Sandra S.; Fisher, Jill K.; Hess, Jay L.; Golub, Todd R.; Armstrong, Scott A.; Akashi, Koichi; Korsmeyer, Stanley J.
In: EMBO Journal, Vol. 24, No. 2, 26.01.2005, p. 368-381.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease
AU - Wang, Jing
AU - Iwasaki, Hiromi
AU - Krivtsov, Andrei
AU - Febbo, Phillip G.
AU - Thorner, Aaron R.
AU - Ernst, Patricia
AU - Anastasiadou, Erna
AU - Kutok, Jeffery L.
AU - Kogan, Scott C.
AU - Zinkel, Sandra S.
AU - Fisher, Jill K.
AU - Hess, Jay L.
AU - Golub, Todd R.
AU - Armstrong, Scott A.
AU - Akashi, Koichi
AU - Korsmeyer, Stanley J.
PY - 2005/1/26
Y1 - 2005/1/26
N2 - Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL-CBP expression and to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/ macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal γ-irradiation or N-ethyl-N-nitrosourea (ENU), MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy-induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/ myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.
AB - Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL-CBP expression and to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/ macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal γ-irradiation or N-ethyl-N-nitrosourea (ENU), MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy-induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/ myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.
UR - http://www.scopus.com/inward/record.url?scp=13444311619&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13444311619&partnerID=8YFLogxK
U2 - 10.1038/sj.emboj.7600521
DO - 10.1038/sj.emboj.7600521
M3 - Article
C2 - 15635450
AN - SCOPUS:13444311619
VL - 24
SP - 368
EP - 381
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 2
ER -