ABSTRACT
The nucleoporin 98 gene (NUP98) has been reported to be fused to 13 partner genes in hematological malignancies with 11p15 translocations. Twelve of them have been identified in patients with myeloid neoplasias and only 1, RAP1GDS1 (4q21), is fused with NUP98 in five patients with T-cell acute lymphoblastic leukemia (T-ALL). Three of these patients coexpressed T and myeloid markers, suggesting the specific association of t(4;11)(q21;p15) with a subset of T-ALL originating from an early progenitor, which has the potential to express mature T-cell antigens as well as myeloid markers. We describe here a new NUP98 partner involved in a t(10;11)(q25;p15) in a patient with acute biphenotypic leukemia, showing coexpression of mature T and myeloid markers. The gene involved, located in 10q25, was identified as ADD3 using 3'-RACE. ADD3 codes for the ubiquitous expressed subunit gamma of the adducin protein, and it seems to play an important role in the skeletal organization of the cell membrane. Both NUP98-ADD3 and ADD3-NUP98 fusion transcripts are expressed in the patient. This is the second partner of NUP98 described in T-ALL. Adducin shares with the product of RAP1GDS1, and with all of the nonhomeobox NUP98 partners, the presence of a region with significant probability of adopting a coiled-coil conformation. This region is always retained in the fusion transcript with the NH(2) terminus FG repeats of NUP98, suggesting an important role in the mechanism of leukemogenesis.
Subject(s)
Chromosomes, Human, Pair 10/ultrastructure , Chromosomes, Human, Pair 11/ultrastructure , Leukemia-Lymphoma, Adult T-Cell/genetics , Oncogene Proteins, Fusion/genetics , Translocation, Genetic , Adult , Amino Acid Motifs , Amino Acid Sequence , Antigens, CD/analysis , Antigens, Neoplasm/analysis , Cell Transformation, Neoplastic/genetics , Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 11/genetics , Humans , Immunophenotyping , In Situ Hybridization, Fluorescence , Leukemia-Lymphoma, Adult T-Cell/pathology , Male , Molecular Sequence Data , Neoplastic Stem Cells/immunology , Oncogene Proteins, Fusion/chemistry , Oncogene Proteins, Fusion/physiology , Protein Conformation , Protein Structure, TertiaryABSTRACT
We report two adult patients with Philadelphia chromosome positive (Ph+) B-cell acute lymphoblastic leukemia (ALL) who presented an additional dic(16;18)(q11;p11) that, to the best of our knowledge, has never been previously reported. Fluorescence in situ hybridization analysis confirmed the translocation and showed it to be dicentric. Both patients were treated for the ALL, but showed refractory disease and died despite aggressive treatment. Similarly to what has been reported with other additional chromosome abnormalities, our cases suggest that the presence of this novel translocation confers an adverse effect to the already poor prognosis of Ph+ ALL.
