COMMENTARY High-Mobility Group a (HMGA) Genes: from Solid to Liquid

COMMENTARY

High-mobility group A (HMGA) genes: from solid to liquid tumours?

J Boultwood1 and JS Wainscoat1

1LRF Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, UK

Leukemia (2005) 19, 195–196. doi:10.1038/sj.leu.2403606 cells.11 Subsequently, HMGA2 rearrangements were reported Published online 16 December 2004 in a case of Richter transformation of a chronic lymphocytic leukaemia,12 and in a case of acute lymphoblastoid leukaemia13 This invited commentary is addressed at the paper by Odero et al and in two patients with myelofibrosis with myeloid metapla- 1 published in this issue of Leukemia. It may come as a surprise sia.14 In addition, in this latter study, the HMGA2 gene was to haematologists to see the high-mobility group A (HMGA) expressed in the haematopoietic cells of 10 of 10 additional genes described as some of the most commonly dysregulated patients bearing no 12q anomalies. genes in human neoplasia, highlighting a role in growth The report by Odero expands the involvement of HMGA2 2 control. So what are the HMGA genes, what is their role in into the myeloid leukaemias. Five of the six patients had MDS, cancer and what is their involvement in leukaemia? the remaining patient had AML. All patients had translocations The HMGA family of proteins, encoded by two related genes or an inversion involving chromosome bands 12q13–15 and HMGA1 and HMGA2, play important functions in transcrip- various other chromosomes. Expression of truncated isoforms of tional regulation, DNA replication and chromatin structure, and HMGA2 was found in two of four cases analysed – similar 3 are frequently referred to as architectural transcription factors. findings to those previously reported in solid tumours. These proteins establish a network of protein–protein and The study by Odero is of importance not only because it protein–DNA interactions, resulting in the formation of en- implicates the deregulation of HMGA2 in the pathogenesis of hanceosomes at promoters and enhancers regulating the some patients with MDS, but also because it acts to illustrate 4 expression of several genes. It is well recognised that HMGA2, how, as with several lymphoid neoplasms, chromosomal in particular, plays a major role in embryonic and foetal growth rearrangements in myeloid malignancies may lead to the and development. Inactivation of HMGA2 in the mouse has generation of a transforming oncogene via overexpression of been shown to impede growth, leading to a ‘pygmy phenotype’, one of the genes at the breakpoint rather than by the generation stressing the importance of this gene in growth control and of a fusion protein. 5 regulation. While the importance of wild-type HMGA2 in growth control, HMGA2 gene dysregulation, as a result of specific chromo- particularly during development, is clear, the mechanism by somal rearrangements, has been seen in a variety of common which the aberrant expression of HMGA2 leads to cancer is not benign mesenchymal tumours (and translocations in benign fully understood. There is some experimental evidence im- tumours possibly a second surprise to haematologists!). Re- plicating HMGA2 in malignant transformation where the critical arrangements of HMGA2 have been found, for example, in event appears to be the expression of truncated HMGA2 6 7 lipomas, adenomas of the parotid gland and uterine leiomyo- isoforms. Transgenic mice with a truncated HMGA2, similar 8 mas. Rearrangements of HMGA2 are also found in malignant to those of human lipomas, are known to acquire a propensity to tumours of mesenchymal origin such as osteosarcomas. The vast develop lymphomas, for example.15 Most recently, HMGA2 has majority of the HMGA2 fusions are out of frame and it is been shown to play a role in the transcriptional regulation of generally considered that over-expression of the N-terminal part genes involved in both the control of the cell cycle and DNA of HMGA2 may be the critical transforming event in tumours. repair.16,17 This may give us an important clue as to the mode of A variety of other tumour types show increased HMGA2 action of HMGA2 in tumorigenesis, since it is well known that expression. For example, an increased HMGA2 expression is deregulation of either the cell cycle or of the DNA repair process associated with the malignant phenotype in pancreatic exocrine may lead to cancer. Further studies are clearly required to fully 9 tissue. Another study found that HMGA2 expression in the elucidate the role of HMGA2 in malignant transformation. peripheral blood of patients with metastatic breast cancer is a The study by Odero clearly highlights the importance of 10 powerful independent indicator for poor survival. HMGA2 in MDS and it seems that the time is now right for a This brief survey brings us to the involvement of HMGA2 in comprehensive study of the involvement of the HMGA genes in 1 leukaemia. The report by Odero et al in this issue of Leukemia haematopoietic malignancies. describes the disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid References disorders. There are just four previous papers making up this genealogy. In 1997, Rommel et al reported that HMGA2 was 1 Odero M, Grand FH, Iqbal S, Ross F, Roman JP, Vizmanos JL et al. expressed in haematopoietic stem cells and in leukaemic Disruption and aberrant expression of HMGA2 as consequent of diverse chromosomal translocations in myeloid disorders. Leuke- Correspondence: Professor JS Wainscoat, LRF Molecular Haematology mia 2005; 19: 245–252. Unit, University of Oxford, Level 4, John Radcliffe Hospital, Oxford, 2 Beitzel B, Bushman F. Construction and analysis of cells lacking OX3 9DU, UK; Fax: þ 01865 221778; E-mail: jim.wainscoat@orh. the HMGA gene family. Nucleic Acids Res 2003; 31: 5025–5032. nh.uk, [email protected] 3 Sgarra R, Rustighi A, Tessari MA, Di B, Altamura S, Fusco A et al. Received 14 October 2004; accepted 21 October 2004; Published Nuclear phosphoproteins HMGA and their relationship with online 16 December 2004 chromatin structure and cancer. FEBS Lett 2004; 574: 1–8. Commentary 196 4 Noro B, Licheri B, Sgarra R, Rustighi A, Tessari MA, Chau KY et al. is expressed in hematopoietic stem cells and in leukaemic cells. Molecular dissection of the architectural transcription factor Leuk Lymphoma 1997; 26: 603–607. HMGA2. Biochemistry 2003; 41: 4569–4577. 12 Santulli B, Kazmierczak B, Napolitano R, Caliendo I, Chiappetta 5 Zhou X, Benson KF, Ashar HR, Chada K. Mutation responsible for G, Bullerdiek J et al. A 12q13 translocation involving the HMGI-C the mouse pygmy phenotype in the developmentally regulated gene in richter transformation of a chronic lymphocytic leukaemia. factor HMGI-C. Nature 1995; 376: 771–774. Cancer Genet Cytogenet 2000; 119: 70–73. 6 Arrigoni G, Doglioni C. Atypical lipomatous tumor: 13 Pierantoni GM, Santulli B, Caliendo I et al. HMGA2 locus molecular characterization. Curr Opin Oncol 2004; 16: rearrangement in a case of acute lymphoblastic leukaemia. Int J 355–358. Oncol 2003; 23: 363–367. 7 Geurts JM, Schoenmakers EF, Roijer E, Astrom AK, Stenman G, van 14 Andrieux J, Demory JL, Dupriez B, Quief S, Plantier I, Roumier C de ven WJ. Identification of NFIB as recurrent translocation partner et al. Dysregulation and overexpression of HMGA2 in myelofi- gene of HMGIC in pleomorphic adenomas. Oncogene 1998; 16: brosis with myeloid metaplasia. Genes Chromosome Cancer 2004; 865–872. 39: 82–87. 8 Mine N, Kurose K, Nagai H, Doi D, Ota Y, Yoneyama K et al. 15 Baldassarre G, Fedele M, Battista S, Vecchione A, Klein-Szanto AJ, Gene fusion involving HMGIC is a frequent aberration in the Santoro M et al. Onset of natural killer cell lymphomas in uterine leiomyomas. J Hum Genet 2001; 46: 408–412. transgenic mice carrying a truncated HMGI-C gene by the chronic 9 Abe N, Wantanabe T, Suzuki Y, Matsumoto N, Masaki T, Mori T stimulation of the IL-2 and IL-15 pathway. Proc Natl Acad Sci USA et al. An increased high-mobility group A2 expression level is 2001; 98: 7970–7975. associated with malignant phenotype in pancreatic exocrine tissue. 16 Borrmann L, Schwanbeck R, Heyduk T, Seebeck B, Rogalla P, Br J Cancer 2003; 89: 2104–2109. Bullerdiek J et al. High mobility group A2 protein and its 10 Langelotz C, Schmid P, Jakob C, Heider U, Wernecke KD, derivatives bind a specific region of the promoter of DNA repair Possinger K et al. Expression of high-mobility-group-protein gene ERCC1 and modulate its activity. Nucleic Acids Res 2003; HMGI-C mRNA in the peripheral blood is an independent poor 31: 6841–6851. prognostic indicator for survival in metastatic breast cancer. Br J 17 Tessari MA, Gostissa M, Altamura S, Sgarra R, Rustighi A, Salvagno Cancer 2003; 88: 1406–1410. C et al. Transcriptional activation of the cyclin A gene by the 11 Rommel B, Rogalla P, Jox A, Kalle CV, Kazmierczak B, Wolf J et al. architectural transcription factor HMGA2. Mol Cell Biol 2003; 23: HMGI-C, a member of the high mobility group family of proteins, 9104–9116.

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