Needed therapy. STAT. Transcription selectivity in 5 minutes

An international research team led by researchers from Vetmeduni Vienna have made an important discovery that could lead to a better understanding of lymphocytic leukemia. They identified the STAT5B protein as crucial for the development of the disease. The BCR/ABL gene, which does not occur among healthy people, has been shown to be a causative agent in the pathogenesis of B-cell acute lymphocytic leukemia. The gene causes white blood cells to become leukemia cells that reproduce out of control. Earlier studies by the research group of Veronika Sexl at Vetmeduni Vienna had already shown that the STAT5 transcription factor was essential for the development of BCR/ABL-induced leukemia. The solution seemed simple: remove STAT5 and the tumor cell dies. But STAT5 actually consists of two genes: STAT5A and STAT5B. The two are very similar and, being 94% identical, had been considered to be functionally equal. Research had therefore focused primarily on the function of STAT5A, as it had appeared to be of greater importance.

In their recently published study in the journal Leukemia, the researchers wanted to know for sure. In their previous experiments, they used to always turned off both genes, as they are situated next to each other on the chromosome. What is exciting is that in recent years cases have been found of patients with mutations that result in STAT5 activation and are assumed to drive disease. Surprisingly, these mutations were found at a much higher frequency in STAT5B than in STAT5A. This finding led the research team to ask: why are mutations found in STAT5B and not in STAT5A? And why is overactivation of STAT5B “good” for the tumor cell?. The team probed these questions by investigating the different function of STAT5A and STAT5B in a mouse model and in human leukemia cells. The absence of STAT5A led to a decrease in cell survival and the formation of colonies of malignant cancer cells. Even more significant effects were observed in the absence of STAT5B. In the mouse model, loss of STAT5B increased interferon response and suppressed transformation.

The opposite scenario was the case in patients with overactive STAT5B: the interferon response against tumor growth was suppressed, and transformation was enhanced. These data demonstrate that STAT5A and STAT5B are “twins with different personalities”, and that STAT5B facilitates leukemogenesis in BCR/ABL leukemia. So it is true that BCR-ABL itself affects STAT proteins in a separate manner. BCR-ABL is a constitutively active cytoplasmic protein tyrosine kinase which activates many intracellular signalling cascades largely overlapping with those activated by cytokine receptors. STAT5 is activated by BCR-ABL and is required for induction and maintenance of BCR-ABL-positive leukemia in mice. However, a former study has shown that BCR-ABL is less effective than cytokines to induce proliferation of cells with reduced STAT5 expression using an RNAi-approach targeting STAT5A and STAT5B simultaneously. For example, interleukin-3 si a cytokine needed for the optimal proliferation and malignancy of bone marrow cancer cells.

Its receptor (IL-3R) activates tyrosine kinases that ultimately drive gene expression linked to cell proliferation. However, IL3R affect preferentially STAT5A and not STAT5B. BCR-ABL affects STAT5A:STAT5B heterodimerization, localization of STAT5A insude the cells and induces aberrant phosphorylation of its Y682 residue. It is assumed that, behind this mechanisms could lie a different pattern of gene activation that would explain the different behavior of leukemic cells exposed to IL-3 or BCR-ABL mutation. These knowledge might help explain the high frequency of STAT5B mutations in hematopoietic tumors. This may be of direct clinical relevance for patients, as a better understanding of the complex role of STAT5B could enable the development of precision medicine strategies to treat diseases. Finally, the data provide molecular evidence that STAT5B may represent a specific therapeutic target in BCR-ABL-positive leukemia although the development of STAT5B-specific small molecule inhibitors may be difficult due to the high homology between STAT5A and STAT5B.

Or maybe not. According to another reserach team, in fact, STAT5 itself could be the solution itself to develop specific leukemia cell inhibitors. A team from the Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin, has discovered that STAT5 may work as a chemical catalyst. The so called Mannich ligations is three-component reactions of an amine, aldehyde, and N- or C-nucleophile, that has been investigated as protein-catalyzed reactions for discovering protein ligands. By assaying more than 17.000 fragments of peptides, scientists were able to synthesize around 25 molecules with increased affinity for STAT5 proteins themselves. The reaction seem to belong to STAT5 proteins since STAT3, another transcription factor involved in blood cancers, did not exert this catalytic property. Neither STAT1 nor the phosphatase SHP2 (turning off STATs) were able to behave like this, nor to bind the developed inhibitors. It is likely that it will be just a matter of time before the precision medicine for certain disease will become more than feasible.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Kollmann S et al., Sexl V. Leukemia 2019 Jan 24.

Berger A et al. Oncotarget 2014 Oct 30; 5(20):9564-76.

Schaller-Schönitz M et al. PLoS One 2014; 9(5):e97243.

Informazioni su Dott. Gianfrancesco Cormaci 1558 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it