Bad neighbors spoil the blood

Vyacheslav Kalinin, "Elements"

There is a firm belief that cancer – a malignant degeneration of a cell – occurs as a result of mutations occurring in it. American scientists have shown that this is not always the case. In experiments on mice, they found that leukemia (blood cancer) can occur due to mutations not only in hematopoietic cells, but also in their microenvironment. The results obtained are of great importance both for theoretical oncology and, possibly, for clinical practice.

It is well known that mutations in hematopoietic stem cells localized in the red bone marrow of flat bones (sternum, pelvic bones) can cause extremely abundant production of white blood cells – leukocytes carrying these mutations. As a result, blood cancer develops – leukemia, or leukemia. Next, we will talk about one of the types of blood cancer that occurs in young children – juvenile myelomonocytic leukemia (juvenile myelomonocytic leukaemia, JMML). JMML refers to myeloproliferative neoplasia (myeloproliferative neoplasm, MPN), in which accumulation of myeloid cells occurs. Currently, this leukemia is treated by removing diseased hematopoietic stem cells with chemotherapy and subsequent transplantation of such cells from a healthy donor. But in about half of the cases after such a procedure, relapses of the disease are observed.

It is known that the risk of developing leukemia, and especially JMML, is high in children with a fairly common hereditary anomaly (1:8000 newborns) – Noonan syndrome. 50% of patients with Noonan syndrome have mutations in the Ptpn11 gene that activate one of the tyrosine protein phosphatases (PTP) encoded by it – SHP2. These mutations have a dominant character: a mutation in one of a pair of genes of the diploid genome is sufficient for the manifestation of the disease. There are also many cases of not hereditary, but sporadic JMML. In these cases, mutations in the genes controlling the signaling pathway of information transmission in the RAS-ERK cell were found in more than 90% of patients in blood cells. Of these, the Ptpn11 gene, already known to us, mutates especially often. Until now, work on the relationship of Ptpn11 mutations with JMML has focused specifically on hematopoietic and blood cells.

The authors of the article under discussion in Nature conducted experiments on mice that were injected with genetically engineered structures that provided selective expression of the Ptpn11 gene with the E76K mutation in certain tissues. The effect of mutations activating the product of the Ptpn11 gene in various cell types was studied.

Fig. 1. On the left – a mutation of the Ptpn11 gene in blood cells in mice and humans causes JMML, one of the myeloproliferative neoplasias (MPN). On the right, the expression of the mutant Ptpn11 gene in the stromal cell of hematopoietic cells causes MPN in mice. Mutant stroma cells produce inflammatory factors, including the CCL3 protein, which cause malignant transformation of normal blood cells, causing JMML-like MPN. MPN development can be hindered by blocking CCL3 activity (CCL3 blocker). A drawing from the popular synopsis to the article under discussion in Nature. As a result, previously available data were confirmed that the expression of Ptpn11E76K in hematopoietic cells causes JMML-like MPN in mice.

In mutant mice, a complex of symptoms characteristic of MPN was observed: a greatly enlarged spleen, a sharp increase in the number of white blood cells, signs of leukemia in the bone marrow and in other tissues and organs.

But it also turned out that in the presence of this mutation in the cells of the stroma (environment of stem hematopoietic cells) The mice also showed manifestations of MPN – despite the absence of mutation in hematopoietic cells and blood cells (Fig. 2). The mutant microenvironment dramatically accelerated the differentiation of hematopoietic cells into mature forms and caused the malignant accumulation of the latter in the blood.

Fig. 2. MPN-specific increase in the size (left) and mass (right) of the spleen in mice with Ptpn11E76K mutation in stroma cells surrounding hematopoietic stem cells. A – mice without mutation, B – mice with mutation. A drawing from the discussed article in Nature.

Moreover, it turned out that if genetically normal hematopoietic stem cells from the mutant microenvironment are transplanted into normal mice, they also develop MPN. Thus, the mutant microenvironment causes some modifications in normal hematopoietic cells that differ from PTPN11E76K mutations, making them malignant. What these modifications are and how they affect the RAS-ERK signaling pathway is still unclear. Finding out the nature of these modifications may help to understand why in 5-10% of JMML cases the genetic nature of the disease remains unknown.

The study of the mechanisms of action of the mutant microenvironment showed that these cells secrete an increased number of biologically active molecules associated with inflammatory processes. These molecules can serve as biomarkers of increased risk of JMML in children. Among them, the chemokine CCL3 turned out to be particularly interesting, the enhanced production of which was found not only in experimental mice, but also in children with JMML. The introduction of Ptpn11E76K mice with CCL3 receptor antagonists blocking its action allowed them to "cure" them of neoplasia. The weight of the spleen decreased (Fig. 3), the number of white cells in the bloodstream decreased, the number of myeloid cells – in the bone marrow, in the spleen and in the bloodstream. This observation seems to be extremely valuable. It is possible that the use of such inhibitors will slow down the development of JMML in patients, will save them from the need for transplantation of hematopoietic stem cells.

3. Six- to seven-month-old mice in which the Ptpn11E76K gene was expressed in the stroma of hematopoietic cells were injected with CCL3 antagonists (B) for 23 days. It shows a decrease in the size of the spleen (left) and its mass (right) compared to "untreated" mice (A). Figure from the discussed article in Nature.

Thus, the conducted studies allowed us to establish the most important fact: mutations in the microenvironment of hematopoietic cells of the bone marrow can induce leukemia. The results obtained open up broad prospects for further research. For example, in Noonan syndrome, various mutations in the Ptpn11 gene are known, as well as mutations in a number of other genes. It is necessary to establish to what extent Ptpn11 mutations and mutations of these other genes in bone marrow microenvironment cells can be associated with the JMML clinic.

The results of the work of American scientists can have an impact on progress in various fields of oncology. It is becoming increasingly clear that the interaction of cancer cells and their microenvironment strongly influences the development of cancer (not only leukemia) and its response to therapy. It is known that inflammatory processes can induce cancer and contribute to its progression. In cancerous tumors, the main effect of tumor-related inflammation is the suppression of the anti-cancer immune response. Therefore, it is interesting to find out how effective in the case of mouse JMML suppression of the action of CCL3 – anti–inflammatory therapy - induces or enhances the anti-leukemia immune response.

Source: Lei Dong et al., Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment // Nature. 2016.

Portal "Eternal youth" http://vechnayamolodost.ru  22.05.2017