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Cooperating
Events in Myeloid Leukemogenesis and Their Reversal 
My research aims to improve our understanding of acute myeloid leukemia
(AML) and to apply this increased understanding to improving treatment
for patients with AML and other malignancies. To this end we are utilizing
a mouse model of human acute promyelocytic leukemia (APL). The recurrent
chromosomal translocation, t(15;17)(q22;q12), is characteristic of APL.
This translocation fuses the retinoic acid receptor a gene (RARa), a member
of the nuclear steroid-thyroid hormone receptor superfamily, with the
gene encoding PML, a nuclear protein that regulates cell growth and survival.
Remarkably, prior to the molecular characterization of the t(15;17) breakpoint,
it was discovered that all-trans retinoic acid, a ligand for RARa, could
induce remission in patients with the PML-RARa fusion by stimulating the
leukemic cells to differentiate into mature neutrophils. We are using
our murine model of APL to identify combinations of genetic changes that
can cause AML, to elucidate the mechanisms by which these events contribute
to leukemogenesis, and to assess molecular targets through which normal
behavior might be restored to leukemic cells.
Although PML-RARA initiates leukemic transformation in transgenic mouse
models of APL, additional molecular events are necessary to complete the
process of transformation. We have demonstrated that the combination of
cytokine stimulation and PML-RARa is sufficient to cause acute leukemia
and are working to identify the molecular mechanisms underpinning this
cooperation. In addition, we have identified karyotypic changes in our
PML-RARA initiated leukemias. It is of interest that we found that the
most common recurring abnormalities in these murine leukemias, +8 and
+15, correspond to the most common additional cytogenetic abnormality
in human APL, trisomy 8. This finding suggests that PML-RARA initiated
murine leukemias are associated with secondary mutations that recapitulate,
in part, the cytogenetic abnormalities of human APL. We are seeking to
identify the genes that drive these karyotypic abnormalities.
C/EBP transcription factors are essential for normal myeloid development
and have been suggested to contribute to both the development of APL and
to the unique sensitivity of APL to retinoic acid. We hypothesized that
increasing the activity of C/EBP factors in myeloid leukemia cells could
revert their leukemic phenotype. To assess this hypothesis, retroviruses
were used to overexpress C/EBPs in myeloid cell lines as well as in murine
APL cells; we found that C/EBP factors suppressed growth and induced partial
maturation in vitro and reversed the leukemic phenotype in vivo. These
findings suggest that modulation of C/EBP activities may provide a new
approach to therapy for AML.
Selected Publictions:
Kogan, SC; Hong, SH; Shultz, DB; Privalsky, ML; Bishop, JM. Leukemia Initiated
by PMLRARa: the PML domain plays a critical role while retinoic acid mediated
transactivation is dispensable. Blood (Plenary Paper) 2000, 95:1541-1550.
Kogan, SC; Brown, DE; Shultz, DB; Tran, BH; Lallemand-Breitenbach, V;
Guillemin, MC; Lagasse, E; Weissman, IL; Bishop, JM. BCL-2 Cooperates
with PMLRARa to Block Neutrophil Differentiation and Initiate Acute Leukemia.
Journal of Experimental Medicine 2001, 193:531-544.
Le Beau, MM; Bitts, S; Davis, EM; Kogan, SC. Recurring Chromosomal Abnormalities
in Leukemia in PML-RARA Transgenic Mice Parallel Human Acute Promyelocytic
Leukemia. Blood, 2002, 99:2985-2991.
Kogan, SC; Ward, JM; Anver, MR; Berman, JJ; Brayton, C; Cardiff, RD; Carter,
JS; de Coronado, S; Downing, JR; Fredrickson, TN; Haines, DC;
Harris, AW; Harris, NL; Hiai, H; Jaffe, ES; MacLennan, ICM; Pandolfi,
PP; Pattengale, PK; Perkins, AS; Simpson, RM; Tuttle, MS; Wong, JF; Morse,
HC III. Bethesda Proposals for Classification of Non-Lymphoid Hematopoietic
Neoplasms in Mice. Blood, 2002, 100:238-245.
Guillein, MC; Raffoux, E; Vitoux, D; Kogan, S; Soihili, H; Lallemand-Breitenbach,
V; Zhu, J; Janin, A; Daniel, MT; Gourmel, B; Degos, L; Dombret, H; Lanotte,
M; de The, H. In vivo activation of cAMP signaling induces growth arrest
and differentiation in acute promyelocytic leukemias. Journal of Experimental
Medicine, 2002, 196:1373-1380.
Truong, BH; Lee, YJ; Lodie, TA; Park, DJ; Perrotti, D; Watanabe, N; Koeffler,
HP; Nakajima, H; Tenen, DG; Kogan, SC. CCAAT/Enhancer Binding Proteins
Repress the Leukemic Phenotype of Acute Myeloid Leukemia. Blood, 2002,
In Press.
Sohal, J; Phan, VT; Chan, PV; Davis, EM; Patel, B; Kelly, LM; Abrams,
T; O’Farrell, AM; Gilliland, DG; LeBeau, MM; Kogan, SC. A model
of APL with FLT3 mutation is responsive to retinoic acid and a receptor
tyrosine kinase inhibitor, SU11657. Blood, 2002, In Press.
Contact Information:
Email: skogan@cc.ucsf.edu
Phone: 415/514-1590
Address: Box 0128, 2340 Sutter, Room N 325
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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