Disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid malignancies

Abstract

Chromosomal translocations that target HMGA2 at chromosome band 12q14 are seen in a variety of malignancies, notably lipoma, pleomorphic salivary adenoma and uterine leiomyoma. Although some HMGA2 fusion genes have been reported, several lines of evidence suggest that the critical pathogenic event is the expression of truncated HMGA2 isoforms. We report here the involvement of HMGA2 in six patients with myeloid neoplasia, dysplastic features and translocations or an inversion involving chromosome bands 12q13-15 and either 7p12, 8q22, 11q23, 12p11, 14q31 or 20q11. Breaks within or very close to HMGA2 were found in all six cases by molecular cytogenetic analysis, leading to overexpression of this gene as assessed by RT-PCR. Truncated transcripts consisting of HMGA2 exons 1-2 or exons 1-3 spliced to intron-derived sequences were identified in two patients, but were not seen in controls. These findings suggest that abnormalities of HMGA2 play an important and previously unsuspected role in myelodysplasia.

The Role of Hmga2 in the Proliferation and Expansion of a Hematopoietic Cell in Myeloproliferative Neoplasms

“…In these studies, the virus was relatively often inserted into the HMGA2 locus, leading to removal of binding sites for let -7 miRNA and clonal outgrowth of hematopoietic cells, which brought a long -term effect including continuous independence of blood transfusion in severe thalassemia 70) . Overexpression and/or truncation of HMGA2 has also been found in patients with PNH and MDS, in which bone marrow failure rather than proliferative hematopoiesis is a common feature 26,68,72) . Bone marrow failure in these disorders is partly due to immunologic HSC injury by autoreactive cytotoxic T lymphocytes (CTLs) that produce tumor necrosis factor (TNF) -α and interferon (IFN) -γ 73 -75) .…”

A cell cycle hypothesis of cooperative oncogenesis (Review)

“…Co-amplification and overexpression of HMGA2 and CDK4 genes at chromosomal region 12q14 occurs in some human cancers such as breast cancers and glioblastomas, and may cooperate to transform cells. HMGA2 is also targeted in cases of myelodysplasia (51). Myelodysplasia is a pathological syndrome that often precedes acute leukemia.…”

t(3;12)(q26;q14) in polycythemia vera is associated with upregulation of the HMGA2 gene

“…In some of them, the partner gene in translocation (or inversion) was identified, although 3 0 RACE-PCR analysis excluded the possibility of a fusion transcript. 6,7 In some of them, aberrant truncated forms of HMGA2 transcripts were described as containing exons 1-3 and a sequence from intron 3 or intron 2, 7 leading to truncation of the acidic carboxyl domain of the protein. 6,7 HMGA2 activation has been reported in myelodysplasia 7 and myelofibrosis with myeloid metaplasia, 6 but never in PV.…”

“…6,7 In some of them, aberrant truncated forms of HMGA2 transcripts were described as containing exons 1-3 and a sequence from intron 3 or intron 2, 7 leading to truncation of the acidic carboxyl domain of the protein. 6,7 HMGA2 activation has been reported in myelodysplasia 7 and myelofibrosis with myeloid metaplasia, 6 but never in PV. Reverse transcription (RT)-PCR and 3 0 RACE-PCR excluded the formation of a 5 0 HMGA2/3 0 TNIK chimeric transcript and, moreover, no difference in the transcriptional pattern of the TNIK gene was observed among PV patients (Figure 1g).…”