HMGA2 involvement in uterine leiomyomas development through angiogenesis activation

Ferrero, Hortensia

doi:10.1016/j.fertnstert.2020.07.044

Cited by 7 publications

(6 citation statements)

References 5 publications

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“…The etiopathogenesis of uterine leiomyoma has been studied from several aspects including their molecular features. It has been shown that three main uterine leiomyoma molecular subtypes exist, including tumors with MED12 mutation, molecular aberrations leading to HMGA2 overexpression, and biallelic loss of FH [ 8 , 10 , 11 , 20 – 23 ]. These mutually exclusive aberrations seem to be a driver event and can be detected in approximately 80–90% of uterine leiomyomas.…”

Section: Discussionmentioning

confidence: 99%

Uterine leiomyoma with RAD51B::NUDT3 fusion: a report of 2 cases

et al. 2023

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Three main uterine leiomyoma molecular subtypes include tumors with MED12 mutation, molecular aberrations leading to HMGA2 overexpression, and biallelic loss of FH. These aberrations are mutually exclusive and can be found in approximately 80–90% of uterine leiomyoma, in which they seem to be a driver event. Approximately 10% of uterine leiomyoma, however, does not belong to any of these categories. Uterine leiomyoma with HMGA2 overexpression is the most common subtype in cellular and second most common category of usual leiomyoma. In some of these tumors, rearrangement of HMGA2 gene is present. The most common fusion partner of HMGA2 gene is RAD51B. Limited data suggests that RAD51B fusions with other genes may be present in uterine leiomyoma. In our study, we described two cases of uterine leiomyoma with RAD51B::NUDT3 fusion, which occur in one case of usual and one case of highly cellular leiomyoma. In both cases, no other driver molecular aberrations were found. The results of our study showed that RAD51::NUDT3 fusion can occur in both usual and cellular leiomyoma. RAD51B may be a fusion partner of multiple genes other than HMGA2 and HMGA1. In these cases, RAD51B fusion seems to be mutually exclusive with other driver aberrations defining molecular leiomyoma subtypes. RAD51B::NUDT3 fusion should be added to the spectrum of fusions which may occur in uterine leiomyoma, which can be of value especially in cellular leiomyoma in the context of differential diagnosis against endometrial stromal tumors.

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Section: Discussionmentioning

confidence: 99%

Uterine leiomyoma with RAD51B::NUDT3 fusion: a report of 2 cases

et al. 2023

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“…Supporting this notion, CD24 induced tumor growth, invasion, and metastasis in different cancers [ 32 ]. HMGA2 upregulation has been associated with the growth of several mesenchymal tumors, including LM [ 9 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. In addition, the 4 tumors analyzed in this study maintained MED12 mutation while expression of HMGA2 increased after long-term culture, supporting the coexistence of both alterations in fibroids [ 10 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Stem Cell Growth and Differentiation in Organ Culture: New Insights for Uterine Fibroid Treatment

et al. 2022

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Organ culture allows for the understanding of normal and tumor cell biology, and tissues generally remain viable for 5–7 days. Strikingly, we determined that myometrial and MED12 mutant leiomyoma cells repopulated cell-depleted tissue slices after 20 days of culture. Using immunofluorescence and quantitative PCR of stem cell and undifferentiated cell markers, we observed clusters of CD49b+ cells in tumor slices. CD49b+ cells, however, were sparsely detected in the myometrial slices. Almost all LM cells strongly expressed Ki67, while only a few myometrial cells were stained for this proliferation marker. The CD73 marker was expressed only in tumor cells, whereas the mesenchymal stem cell receptor KIT was detected only in normal cells. HMGA2 and CD24 showed broader expression patterns and higher signal intensity in leiomyoma than in myometrial cells. In this study, we propose that activating CD49b+ stem cells in myometrium leads to asymmetrical division, giving rise to transit-amplifying KIT+ cells that differentiate to smooth muscle cells. On the contrary, activated leiomyoma CD49b+ cells symmetrically divide to form clusters of stem cells that divide and differentiate to smooth muscle cells without losing proliferation ability. In conclusion, normal and mutant stem cells can proliferate and differentiate in long-term organ culture, constituting a helpful platform for novel therapeutic discovery.

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“…Interestingly, 65% of tumors show mutations in the MED12 gene ( 60 ), and another 25% show aberrations in HMGA2 -driven gene expression ( 15 , 61 ). Uterine fibroids arising from these two mutations show different characteristics; with fibroids driven by MED12 mutations more numerous but smaller in size ( 62 ) compared to fibroids driven by HMGA2 ( 63 ). MED12 has been shown to alter WNT/β-catenin pathway expression ( 64 ).…”

Section: Angiogenesis In Uterine Fibroidsmentioning

confidence: 99%

Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding

Uimari

Subramaniam

Vollenhoven

et al. 2022

Front. Reprod. Health

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Uterine Fibroids, or leiomyomata, affect millions of women world-wide, with a high incidence of 75% within women of reproductive age. In ~30% of patients, uterine fibroids cause menorrhagia, or heavy menstrual bleeding, and more than half of the patients experience symptoms such as heavy menstrual bleeding, pelvic pain, or infertility. Treatment is symptomatic with limited options including hysterectomy as the most radical solution. The genetic foundations of uterine fibroid growth have been traced to somatic driver mutations (MED12, HMGA2, FH−/−, and COL4A5-A6). These also lead to downstream expression of angiogenic factors including IGF-1 and IGF-2, as opposed to the VEGF-driven mechanism found in the angiogenesis of hypoxic tumors. The resulting vasculature supplying the fibroid with nutrients and oxygen is highly irregular. Of particular interest is the formation of a pseudocapsule around intramural fibroids, a unique structure within tumor angiogenesis. These aberrations in vascular architecture and network could explain the heavy menstrual bleeding observed. However, other theories have been proposed such as venous trunks, or venous lakes caused by the blocking of normal blood flow by uterine fibroids, or the increased local action of vasoactive growth factors. Here, we review and discuss the evidence for the various hypotheses proposed.

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HMGA2 involvement in uterine leiomyomas development through angiogenesis activation

Cited by 7 publications

References 5 publications

Uterine leiomyoma with RAD51B::NUDT3 fusion: a report of 2 cases

Uterine leiomyoma with RAD51B::NUDT3 fusion: a report of 2 cases

Stem Cell Growth and Differentiation in Organ Culture: New Insights for Uterine Fibroid Treatment

Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding

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