What is Acute Promyelocytic Leukemia?
Acute promyelocytic leukemia – OPL (MOH according to the FAB classification) is a rather rare variant of acute leukemia, it accounts for no more than 10% of all acute non-lymphoblastic leukemia. A vivid clinical picture and morphological features of the disease allowed Hillestad back in 1957, long before the creation of the FAB classification, to distinguish it as a separate form of acute leukemia.
Causes of Acute Promyelocytic Leukemia
The cause of acute promyelocytic leukemia is the chromosomal translocation t (15; 17) leading to the connection of the retinoic acid receptor gene (RAR-alpha) with the tumor suppressor gene PML [Rabbits, ea 1994, Sanchez-Garcia, ea 1997, Tenen, ea 1997], the product of which forms specific matrix-associated nuclear bodies PML in the nucleus. Cytogenetic analysis reveals translocations capturing chromosomes 15 and 17 in APL patient cells. These specific translocations q (15; 17) (q22; q11.2) were not detected in any other type of myelocytic leukemia or other malignant disease. Translocation (15; 17) interrupts the RAR alpha gene and part of it fuses with the PML locus of chromosome 15, forming the chimeric fusion protein PML-RARa. The PML gene encodes a zinc finger protein, and may be an important transcriptional transcription factor in the process of granulocyte differentiation.
It is assumed that the chimeric protein PML / RAR-a inactivates by the dominant negative mechanism the apoptogenic function of the normal PML protein, forming heterodimers with it. The mechanisms of apoptosis induction during overexpression of PML are not yet entirely clear. The expression of the chimeric protein PML / RAR-a, which causes the inactivation of the normal function of the PML protein, as well as the rearrangement of BCR / ABL, simultaneously leads to changes in the regulation of the cell cycle and to partial blocking of apoptosis induction (it should be noted that, unlike BCR / ABL, the rearrangement PML / RAR-a also causes a differentiation block). As a result of the multidirectional nature of the action of hybrid molecules, cells appear with an increased proliferative potential and, at the same time, resistance to negative regulatory signals and / or adverse environmental conditions. It is assumed that such changes may already be sufficient for the development of at least some forms of hemoblastosis. And, indeed, BCR / ABL or PML / RAR-a rearrangements are often the only genetic changes found in chronic myeloid and acute promyelocytic leukemia, respectively.
Many leukemia-specific genes have been identified, but as a result of the fusion of retinoid acid receptor (RAR alpha) and promyelocyte leukemia (PML) genes, a new interesting example has emerged of these genes leading to acute myelocytic leukemia (APL).
Three different chimeric PML-RARa genes, long (L), medium (M) and short (S) are the result of different types of exon splicing of the PML gene when splicing the translocated RARa gene. Trans retinoid acid (ATRA) leads to the recovery of APL patients, suggesting that a hormone-binding protein is formed during the translocation process. The chimeric PML-RARa protein appears to block myeloid cell differentiation, and ATRA treatment removes this effect.
The genes involved in the pathological process in APM, apparently, lead to structural changes in the normal gene (protooncogen), and its protein product, acting on the host cell, causes malignant degeneration. This protein is normally involved in proliferation and differentiation.
Molecular and clinical studies of APL patients reveal that patient cells can begin to differentiate under the influence of ATRA. The detection of translocation 15; 17 gives a good prognosis. With ATRA therapy, RARa gene remodeling lasts 2–3 weeks and then disappears; after recovery, the normal structure of the RAR gene is restored. The use of ATRA to restore cell maturation and their differentiation into granulocytes leads to the recovery of 85-90% of patients. This is the first example of the treatment of human cancer.
In some cases of APL patients, the RARa gene may be involved in other translocations and rearrangements. Two patients were identified, one with a rearrangement of 11; 17, and the other with a translocation of 15; 17, but without a rearrangement of the PML gene. In both patients, ATRA therapy did not work. Observing the need for sites in front of the PML gene to interact with ATRA increases the need for molecular diagnosis of APL before prescribing or continuing ATRA therapy. The PML-RARa chimeric protein is clinically convenient for diagnosis and observation in the treatment of APL.
Symptoms of Acute Promyelocytic Leukemia
Acute promyelocytic leukemia notes a very rapid course. It is characterized by severe intoxication, bleeding and hypofibrinogenemia (a decrease in blood coagulability) caused by DIC (disseminated intravascular coagulation syndrome). Lymph nodes, liver and spleen are most often not enlarged. In a blood test: anemia, severe thrombocytopenia, in the bone marrow, and usually in peripheral blood, a large percentage of atypical blasts are detected. The nuclei of these leukemic cells in the blood often have a bilobate shape, even more often their shape can be difficult to distinguish because of the abundance of granularity in the cytoplasm. The immediate cause of death of the patient is most often a cerebral hemorrhage.
Acute promyelocytic leukemia is characterized by extreme malignancy of the process, a rapid increase in severe intoxication, severe hemorrhagic syndrome, leading to cerebral hemorrhage and death of the patient.
Acute myeloid leukemia is characterized by a progressive course, severe intoxication and fever, severe anemia, moderate intensity of hemorrhagic manifestations (tendency to bleeding), private ulcerative necrotic lesions of the mucous membranes and skin.
Treatment of Acute Promyelocytic Leukemia
The treatment of acute promyelocytic leukemia can be complicated by two life-threatening conditions – DIC and retinoid syndrome.
DIC-syndrome is caused by death under the influence of cytostatics of leukemia cells and the massive entry of procoagulants from them into the blood. In many cases, heparin treatment is effective. Deficiency of coagulation factors is compensated by cryoprecipitate and freshly frozen plasma.
Tretinoin, unlike cytostatics, promotes the differentiation of leukemia cells. Treatment of acute promyelocytic leukemia with him helps to avoid bleeding, but causes leukocytosis.
Manifestations of retinoid syndrome include fever, shortness of breath, pleural effusion and pericardial effusion, and arterial hypotension. Both leukocytosis and its consequences can be prevented by the appointment of cytostatics.
Mortality of DIC and retinoid syndrome with isolated administration of cytostatics and tretinoin reaches 15-20%. The simultaneous administration of cytostatics and tretinoin reduces mortality, preventing the development of both syndromes.