Causes of Hemoblastosis

What are the Causes of Hemoblastosis?

In the leukemia group, there are tumors that naturally occur under the influence of obvious mutagens (some acute leukemia, chronic myelosis), and tumors that are not induced by them (chronic lymphoproliferative processes), but are often inherited.

Symptoms of Causes of Hemoblastosis

  1. The role of ionizing radiation. Under the influence of ionizing radiation, an increase in the incidence of acute myeloid leukemia in all age groups, acute lymphoblastic leukemia in the group from 2 to 19 years. Dose dependence shows a high frequency of these leukemia in people who were at a distance of up to 1500 m from the epicenter of the explosion. The incidence of acute leukemia is very high among patients with spondylosis who have been irradiated with the spine for pain relief. If in the group of non-irradiated leukemia the frequency was 0.5 per 10,000 per year, then with a total dose of therapeutic irradiation of the spine of 17.5 Gy, the frequency of this disease increased to 16-17 per 10,000, and with a dose of more than 22.5 Gy – up to 72 10,000 a year. There are numerous descriptions of cases of acute myeloblastic, myelomonoblastic leukemia, as well as acute erythromyelosis during irradiation of adult patients with tumor diseases of various localization and lymphogranulomatosis.
  2. The role of chemical mutagens. The possibility of increasing the incidence of leukemia among people exposed to benzene has been known for a long time. The assumption that other chemical factors are mutagens and induce the development of leukemia was quite logical. The chemical mutagens inducing acute myeloid leukemia and erythromyelosis were melphalan, azathioprine, leukeran (chlorobutin), methotrexate, cyclophosphamide. Along with these cytostatic drugs, often used as immunosuppressants, chloramphenicol was also a drug that induces the development of acute myeloid leukemia. There are separate descriptions of acute leukemia in individuals who have been using butadion for a long time, which has some myelotoxic effect. A large number of observations of acute myeloid leukemia as a second disease concerns rheumatoid arthritis, Wegener’s disease and other diseases when cytostatic drugs were used for immunosuppressive purposes.
  3. The role of viruses. There are special viral oncogenes – genes that can force a cell to grow continuously after incorporation into its genome. The identity of viral oncogenes to the cellular oncogenes found in tumor cells indicates the connection of oncogenes with tumor growth and also the connection of some viruses with leukemogenesis. In a tumor such as Burkitt’s lymphoma, oncogenesis serves as a factor provoking an increased proliferation of lymphatic cells. Epstein – Barr. The altered chromosomes are initially directly related to the lymphatic tissue in which the tumor develops, which proves precisely the mutational rather than infectious nature of Burkitt’s lymphoma, in which the dependence of its development on damage to certain chromosomes, as well as on the activation of specific genes in them, is clearly traced. the predominantly viral nature of human leukemia is indicated by the cases of the so-called horizontal spread of leukemia in individual families, when blood relatives or neighbors become ill.
  4. Hereditary factor. Leukemia often occurs in families where leukemia patients of a similar form have already been observed, genetic defects with or without chromosome changes have been reported.

There is evidence in the literature about families where acute and chronic myeloid leukemia is found in several members. The low spontaneous frequency of leukemia eliminates the coincidence of such coincidences. Of particular interest are hereditary diseases, which in themselves are not related to tumor processes, but predispose to the development of leukemia.

First of all, such hereditary diseases are caused by spontaneous chromosome breaks, non-divergence of somatic or sex chromosomes: Down, Blum, Fanconi, Kleinfelter, Turner disease, paR disease. chromosomes 8–9 or 13-14. Even before the introduction of chromosome analysis into practice, W. Krivit, A. Good (1957) noted the relationship of acute leukemia with Down syndrome. In 1961, trisomy of the 21st pair of chromosomes, characteristic of Down syndrome, was described, and it was noted that the frequency of leukemia in this syndrome increases by 18-20 times. In subsequent years, there were many descriptions of patients with Down syndrome and acute congenital leukemia (the so-called acute leukemia that occurs in the first days and months of a child’s life) or with acute leukemia detected at a later age (A. Vorobyov, M. D Brilliant ., 1978). Most cases relate to acute leukemia from a cell – the precursor of myelopoiesis.

Hereditary diseases with nondisjunction in the group of sex chromosomes (Klinefelter, Turner syndromes) are complicated by acute leukemia in people of different ages. Non-divergence of chromosomes of other pairs (8, 9, 13-14) is also combined with the development of acute leukemia, often congenital myeloid.

In Blum and Fanconi syndromes, which are characterized by spontaneous chromosome breaks, an increase in acute myeloid leukemia is described.

In families with hereditary chromosome defects, especially chromosome non-divergence (Down, Klinefelter syndromes), there are frequent cases of acute myeloid leukemia or chronic myeloid leukemia in several members, i.e. leukemia can also be in a family member who does not have a visible chromosome defect.

It should be noted that myeloid leukemia is frequent in families with different genetic defects and in people with non-tumorous genetic diseases. For example, they are described with Marfan syndrome, imperfect osteogenesis, with Gaucher disease. With hereditary diseases affecting the bone marrow, the likelihood of developing myeloid leukemia is especially high.

In addition to such cases, families are described in the literature, some members of which had hereditary neutropenia, others had acute leukemia (Krance et al., 1982). As a rule, acute myeloid leukemia and chronic myeloid leukemia in families with and without genetic diseases with chromosomal defects are characterized by an unfavorable course – the speed of tumor progression and the poor effect of therapy.

Thus, hereditary diseases accompanied by instability of the genotype lead to acute leukemia from the cell – the precursor of myelopoiesis and chronic myelogenous leukemia.

It has now been proven that chronic lymphocytic leukemia is not induced by external factors.

As in the group of myeloid leukemia, familial lymphatic tumors are found. Often there are cases of a combination of chronic lymphocytic leukemia and lymphogranulomatosis in one person or in the same family. At the same time, a high frequency of lymphatic tumors, lymphogranulomatosis is noted in individuals with structural disorders, acromegaly (excessive, disproportionate growth of the limbs and bones of the face), with defects in connective tissue. For example, patients with lymphogranulomatosis often have an extra breast nipple.

Leukemia from the cell – the precursor of lymphopoiesis often develops in hereditary diseases that are associated with immunity defects; chromosome instability detected by the laboratory may not be there.

Genetic diseases with immunity defects with known chromosome instability and without it include:

  1. ataxia – telangiectasia (Louis-Barr disease), where, in addition to the defects reflected in the name, there are thymus hypoplasia and associated defects of cellular immunity, as well as immunoglobulin A, there is a tendency to repeated severe infectious complications;
  2. Wiskott-Aldrich syndrome – eczema, thrombocytopenia and insufficiency of cellular and humoral immunity, leading to infectious complications;
  3. Braton’s disease – agammaglobulinemia.

With these hereditary syndromes, lymphosarcomas and acute lymphoblastic (but not myeloblastic) leukemia are often noted. In families where hereditary immunity defects are observed, the so-called familial lymphatic leukemia and lymphosarcoma are described. Such cases confirm the fact that not the tumors themselves are inherited, but the genetic defects of those cells from which the tumor develops.

Not only hereditary, but also acquired immunity disorders contribute to the occurrence of lymphosarcomas. Deep immunosuppression caused by the use of cytostatic drugs, total irradiation or antilymphocytic serum in combination with cytostatics during transplantation of kidneys or bone marrow, leads to a sharp increase in lymphosarcoma, to a lesser extent – acute lymphoblastic leukemia and cancer of different localization. In this case, the frequency of cancer increases by 2.5 times, and lymphocytic tumors – by 3.5 times.

Also noted are human diseases that occur with impaired production of the endonuclease enzyme responsible for the repair of DNA disorders: xeroderma pigmentosa and Fanconi anemia. With such diseases, a significant increase in the frequency of neoplasms is noted: skin cancer with pigmentary xeroderma, acute leukemia with Fanconi anemia. This shows that the role of mutagens in oncogenesis cannot be accepted as the direct and only reason.

An analysis of the conditions conducive to the development of leukemia, the results of cytogenetic studies that revealed frequent chromosomal changes in the leukemia cell, experiments on the transfer of DNA from this cell to a normal one, leading to its tumor transformation, the development of the leukemia process in accordance with the laws of tumor progression indicate that leukemia have a genetic, mutational basis.

In this case, we are talking about mutations specific for certain forms of leukemia, concerning certain chromosomes and certain regions in them, namely, certain genes responsible for cell proliferation, on the one hand, and for certain stages of differentiation of specific germs in hematopoiesis, on the other. Such specific mutations occur only in conditions of non-specific increased mutability of still non-tumor cells, caused either by the action of radiation, or chemical factors, or viral infections, or hereditary diseases or hereditary defects of the hematopoietic tissue. In turn, the tumor instability of the genotype, which characterizes the already emerged mutant tumor cells, leads to repeated mutations that determine the selection of autonomous subclones and tumor progression.

Thus, the development of leukemia can be represented schematically as a chain of events starting from the stage preceding leukemia, during which a specific mutation appears in one of the normal cells and a specific gene is activated, leading to the appearance of a tumor cell. After, already in the tumor cell, repeated mutations occur, the selection of specifically mutated autonomous subclones is carried out, which leads to the progression and development of the malignant tumor.