Leukemia (from ancient Greek λευκός leukós “white” and αἷμα haima “blood”; literally so white blooded ), also known as (white) blood cancer in German , is a malignant disease of the blood-forming or lymphatic system and, in the broader sense, belongs to the cancer diseases . Another previously used term for this is leukosis .
Leukemia is characterized by the increased formation of dysfunctional precursor cells of white blood cells . These are also called leukemia cells . They spread in the bone marrow , displace the usual blood formation there and, as a rule, also occur to a large extent in the peripheral blood . They can infiltrate the liver , spleen , lymph nodes and other organs and thereby impair their function. The disruption of blood formation reduces the normal blood components. The result is anemia caused by a lack of oxygen-carrying red blood cells , thrombocytopenia , a lack of blood platelets that stop bleeding , and leukopenia , a lack of mature, functional white blood cells.
Depending on the course, a distinction is made between acute and chronic leukemia (see course of disease ). Acute leukemias are life-threatening diseases that, if left untreated, can lead to death within a few weeks or months. Chronic leukemia usually lasts for several years and are often asymptomatic in the early stages.
Chronic leukemia is often discovered by chance through a routine examination and usually begins insidiously. General symptoms of illness such as malaise and fatigue , decreased performance, but also fever , night sweats and weight loss can appear as the first signs . Swelling of the spleen and lymph nodes as well as itching , rashes and infections may also occur.
The symptoms of acute leukemia are very diverse . Often these can arise from complete health and express themselves as a serious clinical picture, e.g. B. paleness, weakness, tendency to bleed with spontaneous bruises or after minor trauma and petechiae . A susceptibility to infections with fever as well as swollen lymph nodes, spleen and liver enlargement and sometimes bone pain are also characteristic. In many cases, patients also complain of increased nosebleeds and gingivitis . Other symptoms include weight loss, loss of appetite, fatigue, and night sweats.
None of these symptoms alone are characteristic of chronic or acute leukemia.
Classification and diagnostics
The classification and diagnosis of leukemia is based on the morphological and immunological properties of the leukemia cells. In recent years, cytogenetic and molecular biological characteristics have also become increasingly important.
Depending on the cell type, a distinction Concerned initially myeloid of lymphoid leukemias. Myeloid leukemias start from the precursor cells of the granulocytes , in a broader sense also the erythrocytes and thrombocytes , lymphatic leukemias affect the lymphocytes and their precursor cells.
Furthermore, a distinction is made between acute and chronic leukemia based on the degree of immaturity of the leukemia cells occurring in the bone marrow and in the blood . In acute leukemia (formerly also called immature-cell leukosis ), there are mainly cells in a very early, immature stage that are almost functionless. In chronic leukemia, more and more leukemia cells can be observed that are significantly more developed and already resemble mature blood cells, but are not yet fully functional.
Forms of leukemia
The main types of leukemia are:
- acute myeloid leukemia (AML)
- chronic myelogenous leukemia (CML) is to the chronic myeloproliferative diseases counted
- acute lymphoblastic leukemia (ALL)
- chronic lymphocytic leukemia (CLL), is one of the low malignant non-Hodgkin lymphomas
If the leukemia originates from the prolymphocytes (a certain form of lymphocyte precursors), one speaks of prolymphocyte leukemia (PLL) because of the significantly more aggressive course of the disease compared to CLL .
Hairy cell leukemia (HCL) is also related to CLL , in which the leukemia originates from very advanced lymphocyte precursors. It is named after the hair-like cytoplasmic extensions of the leukemia cells.
The individual types of leukemia show a typical age distribution. ALL is the most common leukemia in children and less common in adults. AML ranks second in children and is the most common acute leukemia in adults, with a peak over 60 years of age. CLL practically never occurs in children and is a typical form of leukemia in older people. CML is much more common in adults than in children.
Leukemia results from genetic changes in immature blood-forming precursor cells, so that on the one hand these can no longer develop fully into functional blood cells and on the other hand multiply in an uncontrolled manner (see also cancer development ) . It is sufficient to change a single precursor cell, which can push back the healthy components of the blood-forming system through the subsequent uncontrolled growth.
The causes of these genetic changes have not yet been clarified. Particularly in the case of acute forms, the causes are usually unclear and cannot be brought into a causal relationship with pathogenic factors. The following potentially triggering factors are discussed:
- Chemicals, for example benzene ,
- previous treatment with cytostatics (especially alkylating agents ) due to another disease (e.g. a solid tumor ),
- ionizing radiation ,
- various viruses ,
- genetic predisposition.
- Even psychogenic factors are discussed.
Possible causes of leukemia in children
In Germany, 1,800 new children develop cancer each year, around a third of them from leukemia. Here, too, the causes are largely unknown.
A case control study showed that people with Down syndrome had an approximately twenty-fold higher risk of leukemia than the general population.
There are indications that environmental factors (ionizing and non-ionizing radiation as well as pesticides) can be potential risk factors and that a “well trained child's immune system” has a protective effect. A study of children in the city of Basra in southern Iraq found an increase in the leukemia rate by around double between 1993 and 2007. Possible triggers include benzene, which was released into the environment through burning oil fields and improvised gas stations (canister filling), or projectiles made from depleted uranium .
The presumed cause of radioactivity for the leukemia cluster Elbmarsch near Hamburg is controversial. The influence of radioactive emissions on the temporary accumulation of leukemia around Jülich is also unclear .
A population-based case-control study could not show a causal relationship with vaccinations . On the contrary, there is more evidence that early vaccination within the first year of life lowers the risk of disease in children.
The basis of the treatment of leukemia is therapy with cytostatics . Further treatment principles are high-dose therapy with autologous stem cell transplantation and allogeneic bone marrow or stem cell transplantation . A suitable bone marrow donor is required for this, similar to a blood transfusion. Prophylactic or therapeutic radiation therapy is of secondary importance . In recent years, new therapeutic options have emerged through the use of monoclonal antibodies and new drugs that specifically intervene in disease processes, such as imatinib and dasatinib (two tyrosine kinase inhibitors ) for CML and the Philadelphia chromosome- positive ALL or ATRA for promyelocyte leukemia opened. In the therapy of leukemia there are considerable differences between the individual forms; the details of the therapy are presented in the corresponding articles. A specific risk posed by neutropenia occurring during therapy is febrile infections that must be treated with antibiotics.
In the last few years there have been further advances in gene therapy , which now give hope for long-term therapeutic success. For example, some research groups are working on manipulating the T cells of leukemia patients by introducing certain genes so that they can eliminate cancer cells even years later. Some patients with ALL or CLL remained in long-term remission as a result of this therapy .
On November 1, 2013, the USA and on July 29, 2014, the European authorities approved an active ingredient developed by Roche . In patients with chronic lymphocytic leukemia (CLL), after a few days of therapy with the active ingredient obinutuzumab (old name of the active ingredient was afutuzumab ) in combination with the mild chemotherapeutic chlorambucil, a decrease in blood cancer cells can be determined. After completing therapy, more than 20% of the patients no longer showed any symptoms.
In contrast to other types of cancer, which Galenus had already described in antiquity, the blood cancer was not recognized and examined until the 19th century. The strong increase in white blood cells was first described in 1845 by the Scottish doctor John H. Bennett. He described the phenomenon as ulcerated blood and suspected infection as the cause. At around the same time, Rudolf Virchow observed a high increase in white blood cells in a patient, diagnosed “white blood” and in 1847 introduced the medical term “leukemia”. (Virchow understood it to be “a non-reactive, autonomous increase in white blood cells in the peripheral blood that is sharply differentiated from the pyemia”) In 1827 , Alfred Armand Velpeau described a case of leukemia in more detail. The first case of acute lymphoblastic leukemia in a child was described in 1860 by Michael Anton Biermer , a student of Virchow. At the end of the 19th century, pathologists described leukemia as white blood cell neoplasm ; thereafter one could distinguish several manifestations of leukemia. A chemotherapy with aminopterin succeeded in 1947 for the first time Sidney Farber , a pediatric pathologist. However, the remissions achieved did not last long. In the following years, the US National Cancer Institute (NCI) investigated combination therapies in children with acute leukemia (ALL), especially in the 1960s VAMP ( vincristine , amethopterine , mercaptopurine , prednisone ). Initially, long-lasting remissions became apparent, but then the majority of them suffered from severe relapses involving the central nervous system. In the further course, the VAMP therapy was combined with radiation therapy . An initial evaluation of 278 patients in 1979 showed that this combination, understood as “total therapy”, led to significantly longer-lasting remissions. This was the first promising breakthrough.
Leukemia in people with Down syndrome (trisomy 21)
Children with Down syndrome (trisomy 21) have a twenty-fold increased risk of developing acute leukemia. In newborns with trisomy 21, so-called transient leukemia (TL), also known as transient myeloproliferative syndrome (TMD), occurs in five to ten percent , which has all the characteristics of acute megakaryoblastic leukemia ( acute myeloid leukemia , megakaryoblastic subtype / AMkL), however, in the vast majority of cases it resolves spontaneously within the first week of life. In about 20% of these children, however, AMkL (also myeloid leukemia in Down syndrome (ML-DS), see WHO classification) occurs again in the first four years of life, which has the same phenotype. Mutations in the haematopoietic transcription factor GATA1 were found to be causative in both TL and ML-DS . The ML-DS is treated with intensive, customized chemotherapy. Due to the increased sensitivity to chemotherapy, the chances of recovery for ML-DS are more than 85% significantly higher than for AML in children without trisomy 21. Acute lymphoblastic leukemia (ALL) is also more common in children with Down syndrome but associated with a worse prognosis due to the less favorable risk factors and the higher sensitivity to side effects of the therapy.
Aside from the increased risk of leukemia, people with Down syndrome are less likely to develop other forms of cancer. In six independently conducted studies it could be shown that e.g. For example, neuroblastomas , nephroblastomas , abdominal cancer , breast cancer , stomach cancer and colon cancer are very rare: "When compared by age and gender, a person with Down syndrome is 50 to 100 times less likely to die from any form of tissue cancer" than common. In addition to the protective mechanism of the body, which is apparently favored by the additional genetic material, this can also be attributed to the fact that the predisposition to leukemia in particular associated with trisomy 21 is known and an illness due to frequent doctor visits (e.g. because of the susceptibility to respiratory diseases) is often in very early stages can be identified and treated. In addition, most people with Down syndrome live much healthier lives, alcohol and nicotine in particular are rarely actively consumed, which further reduces the risk of developing cancer.
Chromosomal translocations in human leukemia
Reciprocal translocations are typical for leukemia and lymphoma , the exception in solid tumors . Generally speaking, translocations are a characteristic of around three percent of all tumors. In a total of 14,000 different karyotypic changes in tumors, over 100 recurring translocations have been described (as of 1991). Chromosomal changes in haematological diseases are common and varied. A tabular overview should give an impression of the diversity of the phenomena. First, chromosome translocations and then chromosome deletions are listed. The rest of the article is divided into three parts. First, the chromosomal changes in myeloid leukemia are discussed. In the following section the lymphatic leukemias are presented and an exemplary breakpoint examination is presented. Finally, Burkitt's lymphoma will be briefly discussed.
|Oncogenes in leukemia - translocations|
|Tyrosine - kinases||c-abl / bcr||t (9; 22) (q34; q11)||CML||95%|
|c-abl / bcr||t (9; 22) (q34; q11)||ALLES||10%|
|axl||t (;) (;)||CML||? %|
|TF||myc / Ig genes||t (8; 14) (q24; q32)||BL||100%|
|E2A / PBX||t (1; 19) (q23; p13)||pre-B-ALL||10%|
|E2A / HLF||t (17; 19) (q22; p13)||pre-B-ALL||10%|
|Valley-1 / TCR||t (1; 14) (p32; q11)||T-ALL||20%|
|Valley-1 / SIL||t (1;) (p32;)||T-ALL||20%|
|Valley-2 / TCR||t (7; 9) (q35; p13)||T-ALL||10%|
|Lyl-1 / TCR||t (7; 19) (q35; p13)||T-ALL||5%|
|Ttg-1 / TCR||t (11; 14) (pls; q11)||T-ALL||10%|
|Ttg-2 / TCR||t (11; 14) (p13; q11)||T-ALL||−10%|
|HD genes:||Hox-11 / TCR||t (10; 14) (q24; q11)||T-ALL||7%|
|Receptors :||RARA / PML||t (15; 17) (q21; q21)||PML||100%|
|bcl genes:||bcl-1 / Ig||t (11; 14) (q32; q21)||CentroCyt||30%|
|bcl-2 / Ig||t (14; 18) (q13; q32)||Foll|
|bcl-3 / Ig||t (14; 19) (q32; q13)||CLL|
|Other:||DEK / CAN||t (6; 9) (p23; q34)||AML / MDS|
|SET / CAN||t (;) (;)||AML, MDS|
|MLL||t (11q23)||AML, ALL|
|TAN-1||t (7; 9) (q34; q34.3)||T-ALL||42%|
|AML-1||t (8; 21)||AML|
|IL-3||t (5; 14) (q31; q32) pre-B-ALL|
The following table gives an overview of the chromosomal deletions in various human leukemias.
|Oncogenes in leukemia - deletions|
|RB-1||Ph1 + -ALL||30%|
Chronic myeloid leukemia (CML) translocations
In chronic myeloid leukemia , 95 percent of all cases examined so far result in a fusion of the c-abl gene on chromosome 9q34 with the bcr gene on chromosome 22q11, resulting in an altered chromosome, the Philadelphia- Chromosome , and the expression of a chimeric protein, the abl / bcr product, which occurs in three variants as p190, p210 and p230 and has tyrosine kinase activity. The fusion protein results in a constitutive activation of abl-tyrosine kinase and stimulates various signaling pathways, e.g. B. p21 Ras, PI3 Kinase, Jun, myc.
Translocations in Acute Myeloid Leukemia (AML)
The acute myeloid leukemia there is a variety of different mutations . In AML, mutations in the N-ras locus are found in up to 50 percent of the cases examined, mutations in p53 in approx. Five percent of the cases examined, and mutations in the RB-1 gene and in in less than three percent of the cases examined approx. 20 percent changes in the WT-1 locus. Fusions of SET / CAN , DEK / CAN , MLL and AML-1 genes have been described in isolated cases . The oncogenes involved are characterized in more detail below.
Translocations in other myeloid leukemias
In acute myelomonocytic leukemia (AMML), mutations are often found in the RB-1 locus. A special feature of AML is promyelocytic leukemia, in which a translocation t (15; 17) (q21; q21) is described in more than 95 percent of the cases examined, resulting in a fusion of PML and RARa. The human trithorax homolog is found on chromosome 11q23. The HRX translocations are found in biphenotypic leukemias. Trithorax is ALL-1.
Translocations in T-cell leukemia
The following table provides an overview of the occurrence of translocations in acute T-cell leukemia.
|Translocations in T-cell leukemia|
|t (8; 14) (q24; q11)||c-myc||8q24||TCR-alpha / delta||14q11|
|t (7; 19) (q35; p13)||TCR-beta||7q35||Lyl-1||19p13|
|t (1; 14) (p32; q11)||Valley-1 (Scl, Tcl-5)||1p32||TCR-alpha / delta||14q11|
|t (7; 9) (q35; q34)||TCR-beta||7q35||Valley-2||9q34|
|t (11; 14) (pl5; q11)||Rhom-1 (Ttg-1)||11p15||TCR-alpha / delta||14q11|
|t (11; 14) (p13; q11)||Rhom-2 (Ttg-2)||11p13||TCR-alpha / delta||14q11|
|t (7; 11) (q35; p13)||TCR-beta||7q35||Rhom-2||11p13|
|t (10; 14) (q24; q11)||Hox-11 (Tcl-3)||10q24||TCR-alpha / delta||14q11|
|t (7; 10) (q35; q24)||TCR-beta||7q35||Hox-11||10q24|
|t (7; 9) (q34; q34.3)||TCR-beta||7q34||Tan-1||9q34.3|
All affected proto-oncogenic transcription factors (c-myc, Lyl-1, Tal-1,2) are helix-loop-helix proteins; Rhom-1,2 (Ttg-1,2) are LIM domain proteins, Hox-11 (Tcl-3) is a Homeoboxgen and Tan-1 is a notch homolog. TCR-beta or TCR-alpha / delta are always involved. Comparatively consistent mutations in T-ALLs are also found in p53 Jonveaux and in the RB locus Ahuja and Ginsberg, however, without translocations into the area of rearranged loci. If one examines the different loci, one finds the following distribution of the translocating regions.
Translocate into the TCR-alpha / delta region = 14q11:
|Chromosomal location of TCR-alpha / delta-translocating oncogenes|
Translocate into the TCR-beta region = 7q35:
|Chromosomal localization of TCR-beta translocating oncogenes|
The listed translocations at T-ALL have a number of things in common. Two typical coding regions are affected: TCR genes and transcription factors. The affected allele of the TCR as a structural gene is always destroyed and the affected allele of the transcription factor as a structural gene is intact, but its regulation is disturbed. Most of the time, the affected transcription factors are genes that are foreign to the cell line. Their function is usually assumed in the context of cell differentiation. In the area of 11p13, the breakpoints are clustered in a small area, independent of the translocating partner chromosome. In addition, the translocations take place in immature cells, so that one must conclude that an aberrant expression of transcription factors involved in the cell differentiation of non-lymphatic tissue in primitive lymphoid tissue can play a significant part in the malignant transformation.
- Chronic myeloproliferative diseases related to CML , which are less common but mainly affect blood cells other than leukocytes, are:
- In myelodysplastic syndromes, too, there is a malfunction of the blood-forming stem cells . In contrast to the leukaemias, however, there is no uncontrolled multiplication of these.
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