The human formin-binding protein 17 (FBP17) interacts with sorting nexin, SNX2, and is an MLL-fusion partner in acute myelogeneous leukemia

doi:10.1073/pnas.121433898

The human formin-binding protein 17 (FBP17) interacts with sorting nexin, SNX2, and is an MLL-fusion partner in acute myelogeneous leukemia

Departments of ^*Pediatric Hematology and Oncology, and ^‖Pathology, University of Giessen, 35392 Giessen, Germany; ^‡Children's Cancer Research Institute and Ludwig Boltzmann Institute for Cytogenetic Diagnosis, Saint Anna Kinderspital, 1090 Vienna, Austria; ^§Department of Genetics, University of Erlangen, 91058 Erlangen, Germany; ^¶Department of Clinical Chemistry, Rigshospitalet, 2100 Copenhagen, Denmark; and ^**Department of Hematology, Oncology, and Tumor Immunology, Robert-Rössle Clinic, Humboldt-University, 13125 Berlin, Germany

Edited by Janet D. Rowley, University of Chicago Medical Center, Chicago, IL, and approved April 27, 2001 (received for review September 11, 2000)

Abstract

We have cloned a fusion partner of the MLL gene at 11q23 and identified it as the gene encoding the human formin-binding protein 17, FBP17. It maps to chromosome 9q34 centromeric to ABL. The gene fusion results from a complex chromosome rearrangement that was resolved by fluorescence in situ hybridization with various probes on chromosomes 9 and 11 as an ins(11;9)(q23;q34)inv(11)(q13q23). The rearrangement resulted in a 5′-MLL/FBP17-3′ fusion mRNA. We retrovirally transduced murine-myeloid progenitor cells with MLL/FBP17 to test its transforming ability. In contrast to MLL/ENL, MLL/ELL and other MLL-fusion genes, MLL/FBP17 did not give a positive readout in a serial replating assay. Therefore, we assume that additional cooperating genetic abnormalities might be needed to establish a full malignant phenotype. FBP17 consists of a C-terminal Src homology 3 domain and an N-terminal region that is homologous to the cell division cycle protein, cdc15, a regulator of the actin cytoskeleton in Schizosaccharomyces pombe. Both domains are separated by a consensus Rho-binding motif that has been identified in different Rho-interaction partners such as Rhotekin and Rhophilin. We evaluated whether FBP17 and members of the Rho family interact in vivo with a yeast two-hybrid assay. None of the various Rho proteins tested, however, interacted with FBP17. We screened a human kidney library and identified a sorting nexin, SNX2, as a protein interaction partner of FBP17. These data provide a link between the epidermal growth factor receptor pathway and an MLL fusion protein.

Footnotes

↵ † U.F. and G.R. contributed equally to this work.
↵ ‡‡ To whom reprint requests should be addressed at: Children's University Hospital, Pediatric Hematology and Oncology, Feulgenstrsse 12, D-35392 Giessen, Germany. E-mail: Arndt.Borkhardt{at}paediat.med.uni-giessen.de.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF265550).
Abbreviations:

FISH,

fluorescence in situ hybridization;

RT-PCR,

reverse transcriptase–PCR;

AML,

acute myeloid leukemias;

FBP,

formin binding protein;

BM,

bone marrow;

CFC,

colony-forming assay;

SNX,

sorting nexin;

GFP,

green fluorescent protein;

EGFR,

epidermal growth factor receptor