FHL2 interacts with CALM and is highly expressed in acute erythroid leukemia

Z Pašaliç,V Jurinoviç,A Krause,P A Greif,S K Bohlander,P M Kakadia,L Fröhlich-Archangelo,M Mulaw,B Tizazu

doi:10.1038/bcj.2011.40

Abstract

The t(10;11)(p13;q14) translocation results in the fusion of the CALM (clathrin assembly lymphoid myeloid leukemia protein) and AF10 genes. This translocation is observed in acute myeloblastic leukemia (AML M6), acute lymphoblastic leukemia (ALL) and malignant lymphoma. Using a yeast two-hybrid screen, the four and a half LIM domain protein 2 (FHL2) was identified as a CALM interacting protein. Recently, high expression of FHL2 in breast, gastric, colon, lung as well as in prostate cancer was shown to be associated with an adverse prognosis. The interaction between CALM and FHL2 was confirmed by glutathione S-transferase-pulldown assay and co-immunoprecipitation experiments. The FHL2 interaction domain of CALM was mapped to amino acids 294–335 of CALM. The transcriptional activation capacity of FHL2 was reduced by CALM, but not by CALM/AF10, which suggests that regulation of FHL2 by CALM might be disturbed in CALM/AF10-positive leukemia. Extremely high expression of FHL2 was seen in acute erythroid leukemia (AML M6). FHL2 was also highly expressed in chronic myeloid leukemia and in AML with complex aberrant karyotype. These results suggest that FHL2 may play an important role in leukemogenesis, especially in the case of AML M6.

Highlights

Chromosomal translocations play a crucial role in the development of many types of leukemia, lymphomas, sarcomas and solid tumors.1 In translocations, normal gene function can be altered in two different ways: either by the formation of fusion genes or by transcriptional deregulation of genes adjacent to the breakpoints.2 The t(10;11)(p12;q14) translocation results in the fusion of Clathrin assembly lymphoid myeloid leukemia (CALM) on chromosome 11 band q14 with AF10 (MLLT10) on chromosome 10 band p12.3 The CALM/AF10 fusion is observed in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and malignant lymphoma, and has a poor prognosis4,5 (Figure 1a).The AF10 gene was first identified as the fusion partner of MLL in AML patients carrying a t(10;11)(p12;q23) translocation.6 AF10 codes for a 1027-amino-acid-long putative zinc-finger transcription factor
We show that FHL2 interacts with CALM and that it is highly expressed in acute erythroid leukemia (AML M6), suggesting an important role for FHL2 in leukemogenesis, especially in the development of erythroleukemia
The CALM/AF10 fusion is found in myeloid and lymphoid lineage acute leukemias

Summary

Introduction

Chromosomal translocations play a crucial role in the development of many types of leukemia, lymphomas, sarcomas and solid tumors. In translocations, normal gene function can be altered in two different ways: either by the formation of fusion genes or by transcriptional deregulation of genes adjacent to the breakpoints. The t(10;11)(p12;q14) translocation results in the fusion of CALM (clathrin assembly lymphoid myeloid leukemia protein) on chromosome 11 band q14 with AF10 (MLLT10) on chromosome 10 band p12.3 The CALM/AF10 fusion is observed in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and malignant lymphoma, and has a poor prognosis (Figure 1a).The AF10 gene was first identified as the fusion partner of MLL in AML patients carrying a t(10;11)(p12;q23) translocation. AF10 codes for a 1027-amino-acid-long putative zinc-finger transcription factor. The t(10;11)(p12;q14) translocation results in the fusion of CALM (clathrin assembly lymphoid myeloid leukemia protein) on chromosome 11 band q14 with AF10 (MLLT10) on chromosome 10 band p12.3 The CALM/AF10 fusion is observed in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and malignant lymphoma, and has a poor prognosis (Figure 1a). The AF10 gene was first identified as the fusion partner of MLL in AML patients carrying a t(10;11)(p12;q23) translocation.. AF10 codes for a 1027-amino-acid-long putative zinc-finger transcription factor. The Drosophila homolog of AF10, alhambra, The CALM gene is located on chromosomes 11 band q14 and encodes a 652-amino-acid-long protein. CALM is ubiquitously expressed and homologous to the neuron-specific clathrin assembly protein AP180.9 CALM is mainly located in the cytoplasm and along the membrane in clathrin-coated pits.. CALM is ubiquitously expressed and homologous to the neuron-specific clathrin assembly protein AP180.9 CALM is mainly located in the cytoplasm and along the membrane in clathrin-coated pits. CALM does shuttle between the cytoplasm and the nucleus, permitting CALM and the nucleolar protein CATS to interact.

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