The t(3;5) in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) creates a fusion product in which the amino-terminus of nucleophosmin (NPM), a nucleolar shuttle protein, is linked to the novel protein myelodysplasia/myeloid leukemia factor 1 (MLF1). The NPM portion of NPM-MLF1 contains an oligomerization motif that mediates self- association, association with normal NPM, and nuclear targeting; the importance of these (and other) NPM functions in NPM-MLF1-mediated MDS and AML is unknown. The normally cytoplasmic MLF1 protein, which lacks recognized functional motifs, is expressed in some leukemic cell lines but not in t(3;5)- positive cells; the role of MLF1 in normal hematopoiesis has not been determined. NPM-MLF1 can inhibit the G-CSF- mediated survival and, hence, the differentiation of myeloid precursor cells in a manner consistent with the proposed pathogenesis of MDS; MDS progression to AML probably requires additional mutations that cooperate with NPM-MLF1. To understand how NPM-MLF1 contributes to the genesis of MDS and AML, the funtionally -critical motifs in the NPM and MLF1 portions of the fusion that mediate its ability to block myeloid cell survival/differentiation will first be identified. Next, the hypothesis that NPM-MLF1 interferes with hematopoietic development to produce MDS and AML will be tested in mice programmed to express the fusion; as a corollary, the necessity for cooperating mutations in the induction AML by NPM-MLF1 will be determined and, if required, the involved genes will be identified. Finally, the role of MLF1 in normal growth and development will be defined to better understand how its alteration produces MDS and AML by determining the Mlf1 expression pattern in fetal and adult mice, by targeted disruption of the gene, and by assessing the effects of Mlf1 absence, or its aberrant expression, on hematopoietic differentiation of ES cells in vitro. These studies should yield valuable insight into the regulatory pathways disrupted by NPM-MLF1 in myelodysplastic (preleukemic) cells, and perhaps into the pathobiology of AML in general.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076301-04
Application #
6329005
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mufson, R Allan
Project Start
1997-12-15
Project End
2002-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
4
Fiscal Year
2001
Total Cost
$307,062
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Falini, B; Bigerna, B; Pucciarini, A et al. (2006) Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): a comparison with NPMc+ AML. Leukemia 20:368-71
Hanissian, Silva H; Akbar, Umar; Teng, Bin et al. (2004) cDNA cloning and characterization of a novel gene encoding the MLF1-interacting protein MLF1IP. Oncogene 23:3700-7
Kuefer, Martin U; Chinwalla, Vandana; Zeleznik-Le, Nancy J et al. (2003) Characterization of the MLL partner gene AF15q14 involved in t(11;15)(q23;q14). Oncogene 22:1418-24
Lim, Raelene; Winteringham, Louise N; Williams, James H et al. (2002) MADM, a novel adaptor protein that mediates phosphorylation of the 14-3-3 binding site of myeloid leukemia factor 1. J Biol Chem 277:40997-1008
Hansen-Hagge, T E; Schafer, M; Kiyoi, H et al. (2002) Disruption of the RanBP17/Hox11L2 region by recombination with the TCRdelta locus in acute lymphoblastic leukemias with t(5;14)(q34;q11). Leukemia 16:2205-12
Duyster, J; Bai, R Y; Morris, S W (2001) Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20:5623-37
Morris, S W; Xue, L; Ma, Z et al. (2001) Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma. Br J Haematol 113:275-95
Hitzler, J K; Witte, D P; Jenkins, N A et al. (1999) cDNA cloning, expression pattern, and chromosomal localization of Mlf1, murine homologue of a gene involved in myelodysplasia and acute myeloid leukemia. Am J Pathol 155:53-9
Xie, J; Briggs, J A; Morris, S W et al. (1997) MNDA binds NPM/B23 and the NPM-MLF1 chimera generated by the t(3;5) associated with myelodysplastic syndrome and acute myeloid leukemia. Exp Hematol 25:1111-7