Leukemia

Leukemia
Specialty	Hematology

Leukemia (leukaemia in Commonwealth English) is a cancer of the blood or bone marrow characterized by an abnormal proliferation of white blood cells (leukocytes).

Overview

The word leukemia refers to a group of cancers which affect the cells of the immune system. This includes white blood cells, also known as leukocytes, or lymphocytes. Lymphocytes include the antibody secreting B cells and both cytotoxic T cells and T helper cells. In the 19th century, it was seen as one single, homogenous deadly disease, characterized by a white (leuko-) appearance of blood samples. Leukemia was first recognized by the German pathologist Rudolf Virchow in 1847 and the first case was described by British pathologist John Hughes Bennett in 1845.

Leukemia arises in the bone marrow. The bone marrow produces several major types of blood cells.

1. Red blood cells (technically termed erythrocytes) contain hemoglobin and are responsible for carrying oxygen to the body.
2. Leukocytes are responsible for fighting infection via the innate immune response. They include the macrophages, basophils, neutrophils, eosinophils, and dendritic cells.
3. Lymphocytes are also responsible for fighting infection via the adaptive immune response. These include the aforementioned B and T cells.
4. Platelets assist with blood clotting.

Leukemia is characterised by an excessive proliferation of either abnormal leukocytic or lymphocytic precursors overcrowding the bone marrow and often spilling out into the peripheral blood. This proliferation is a result of a variety of possible genetic mutations, all of which can be caused by a multitude of factors. The infiltration of the bone marrow results in decreased production and function of normal blood cells. Leukemia, dependent on the type, can spread to the lymph nodes, spleen, liver, central nervous system and other organs or tissues, causing the affected area to swell.

Symptoms

Damage to the bone marrow results in a lack of blood platelets, which are important in the blood clotting process. This means people with leukemia may become bruised, bleed excessively (such as nose bleeds), or develop pinprick bleeds (petechiae). Also, due to lower red blood cell counts,anemia is a major symptom for diagnosing leukemia.

White blood cells, which are involved in fighting pathogens, may be suppressed or dysfunctional, putting the patient at risk of infection.

Finally, the red blood cell deficiency leads to anemia, which may cause shortness of breath and fatigue. Bone or joint pain may occur because of cancer spreading to these areas. Headaches and vomiting are indicative of the cancer having disseminated to the central nervous system.

Enlarged lymph nodes or splenomegaly (an enlarged spleen) may occur in some types. This indicates that the cancer may have spread to the lymphatic system. All symptoms may also be attributable to other diseases; for diagnosis, blood tests and a bone marrow biopsy are required.

Some other related symptoms:

• Fever, chills, and other flu-like symptoms;
• Weakness and fatigue;
• Loss of appetite and/or weight;
• Swollen or bleeding gums;
• Sweating, especially at night;
• Bone or joint pain.
• Neurological symptoms (headache, vomiting, paralysis, seizures) due to migration of the cancer to the brain (acute leukemias). This would require a spinal tap as additional diagnosis.
• Swelling of the testicle(s).
• Skin symptoms

Four major types

Leukemia is a broad term covering a spectrum of diseases.

Acute vs. chronic

Leukemia is clinically and pathologically split in to its acute and chronic forms.

• Acute leukemias are characterised by the rapid growth of immature blood cells. This crowding makes the bone marrow unable to produce healthy blood cells. Acute forms of leukemia can occur in children and young adults. (In fact, it is a more common cause of death for children in the US than any other type of malignant disease). Immediate treatment is required in acute leukemias due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. If left untreated, the patient will die within months or even weeks.

• Chronic leukemias are distinguished by the excessive buildup of relatively mature, but still abnormal, blood cells. Typically taking months to years to progress, the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy.

Lymphoid vs. myeloid

Furthermore, the diseases are classified according to the type of abnormal cell found most in the blood.

• When leukemia affects lymphoid cells, it is called lymphocytic leukemia.

• When myeloid cells (leukocytes) are affected, the disease is called myeloid or myelogenous leukemia.

Prevalence of the four major types

Combining these two classifications provides a total of four main categories:

• Acute lymphocytic leukemia (ALL) is the most common type of leukemia in young children. This disease also affects adults, especially those age 65 and older.
• Acute myelogenous leukemia (AML) occurs more commonly in adults than in children. This type of leukemia was previously called acute nonlymphocytic leukemia.
• Chronic lymphocytic leukemia (CLL) most often affects adults over the age of 55. It sometimes occurs in younger adults, but it almost never affects children.
• Chronic myelogenous leukemia (CML) occurs mainly in adults. A very small number of children also develop this disease.

The most common forms in adults are AML and CLL, whereas in children ALL is more prevalent.

Disease Demographics and Children

1 out of every three cancer cases in children under 15 is of the leukemia type, with a vast majority of them (80%) the acute type. By the age of 20, 1 out of every cases of childhood malignancy is leukemia. Hence, leukemia is the leading malignant disease amongst both children and young adults. Acute lymphocytic leukemia, or ALL, most often occurs around the age of 2 to 3.

ALL occurs at a higher rate amongst white children compared to other ethnicities, however white children have an overall higher survival rate despite similar treatment. This may be due to genetic predispositions leading to minorities having a higher initial whit e blood cell count than white children, leading to faster towards advanced-staged leukemia. However, aggressive treatment can help to correct this disparity.

Amongst infants, leukemia is very rare, usually of the AML type, and generally fatal. For older children, leukemia treatment has an 80% success rate.

Genetic Factors Leading to Leukemia

As already stated, leukemia developmed is due to excessive proliferation of abnormal (cancerous) myeloid or lymphocytic cells. The molecular genetic mechanisms for why these proliferations occur is very diverse and complex. However, in the end the premise for all of the defects is the same: mutations that lead to either increased expression or decreased expression of certain gene sequences that leads to signaling pathways that promotes increased growth of the hematopoietic stem cell (HSC). The HSC is the original precursor of all circulatory and immune related cells found in the bone marrow.

These mutations include abnormal oncogenes, chromosomal translocations, and of course modifications in rates of transcription of the aforementioned genetic sequences.

The HOX gene family is particular important. These genes encode for important regulatory transcription enzymes (proteins). For example, translocation of the mixed-lineage leukemia (MLL) gene sequence results in a variety of MLLs fused with other proten byproducts. These hybrids (most commonly MLL:AF4 and MLL:ENL) transcribe the HOX gene sequence at a greater rate, leading to greater HSC cell growth.

Another example would be the cleaving of DNA topoisomerase II, which induces leukemia development. Cleavage allows for the nicking of opposite strands of the MLL gene, creating long overhangs and thus a mutated gene, as the gene attempts to repair itself. This in turn leads to mutation of the MLL gene.

Certain naturally occuring compounds have been cited to be able to cleave DNA topoisomerase II:

• Quinolones
• Catechins

Other compounds or foods containing certain compounds known to at least deactive or interact with the protein and are possible leukemia inducers (or at least make the possibility of developing leukemia more probable) are listed:

• - Caffeine
• - Wine
• - Beans
• - Soy (isoflavanoids)
• - Red Wine (quercetin)

Leukemia and Down Syndrome

It is believed that there is a connection between certain forms of leukemia and Down syndrome. Much of the reasoning for this remains unknown. However, recent studies have shown that the GATA 1 HSC growth transcription factor may be involved (Wechsler J, Greene M, et al) due to a mutation in GATA 1's gene sequence, leading to a shortening of its chain. Hence, GATA 1 binds to gene sequences encoding regulation of HSC growth at a lower rate.

In one study, it was determinted that a child born with a birth defect would have a much greater chance of developing leukemia as compared to a healthy child (2.7 to 1) (Agha M, Williams JI, et al). Another study showed that a child with Down syndrome would be 10 times more likely to develop leukemia (Patja K, Pukkala E, et al).

The Familial Connection

Many studies have been carried out to determine whether or not there is a hereditary link with leukemia and family history. While nothing is proven, several studies revealed some interesting correlations:

• An increased risk of developing childhool ALL if a primary (parent or sibling) or secondary (aunt/uncle, grandparents) also had ALL at some stage in their lives (Infante-Rivard C and Guiguet M).
• An increased risk of developing CLL if two or more family members had a blood disorder (Capalbo S, Callea V, et al.).
• An increased risk of developing childhood ALL and a primary or secondary family member having an autoimmune disease, especially thyroid conditions (Perillat-Menegaux F, Clavel J, et al.).
• An increased risk of developing ALL or AML if a primary or secondary relative had a solid tumor or a hematological neoplasm (i.e. - Hodgkin's disease) (Perrillat F, Clavel K, et al.).

One of the most probable explanations for why these correlations occurs is not because of the possibility of passing down certain genes. Instead, a person is more likely to be exposed to the same environment that a previous family member was also exposed too, based on geographical area and economic situation. External causes in the development of leukemia will be discussed below.

Causes

There is a wide variety of potential factors that could be involved that cause the genetic mutations in DNA necessary for modifiction of HSC growth rates and differentiation. While these mutations may occur spontaneously, many possible external causative agents have been identified. One of the most powerful tools for identifying potential causative agents is the employment of leukemia clusters. A leukemia cluster is a geographical region where there is an unusually high rate of leukemia. By using clusters, epidemiologists can look for patterns (i.e. 10 clusters were all located near a petrochemical plant) to identify potential leukemia-inducing substances. In almost all leukemia clusters, there has been a high concentration of a particular compound in the region's air, soil, or water.

Viruses have also been linked to some forms of leukemia. Certain cases of ALL are associated with viral infections by either the human immunodeficiency virus (HIV, responsible for AIDS) or human T-lymphotropic virus (HTLV-1 and -2, causing adult T-cell leukemia/lymphoma).

Diet has also been cited as a potential factor in leukemia development. One study has shown that diets high in [vitamin C] and [potassium] at an early age can help inhibit development of the disease (Kwan ML, Block G, et al.).

Immunosuppression

The usage of immunosuppressive agents to prevent a graft rejection, such as a kidney transplant, is a likely culprit of pediatric leukemia. Immunosuppression coupled with Epstein-Barr virus infection are associated with the development of leukemia in these cases. To handle this, physicians must develop an effective treatment regimen following the development of the malignancy. Carefully controlled and timed immunosuppressive withdrawal coupled with administration of chemotherapy is necessary to achieve remission. To ensure that the graft is not rejected, the physicians must perfectly time remission with resumed administration of immunosuppression (Praghakaran K, Wise B, et al.).

Recent studies have shown that a child exposed to a variety of infections at an early age have a lower risk of developing leukemia compared to children not exposed to as many pathogens, particularly involving day care centers or other social engagements (Gilham C, Peto J, et al.).

Mutagenic Agents

A variety of chemical and [radioactive] substances, as well as sources of their emittance, have been cited as potential causes of leukemia.

Benzene is cited more than any other chemical when carcinogenicity is concerned. As a matter of fact, it is the only proven carcinogenic agent (Steffen C, Auclerc MF, et al.). Polycylic aromatic hydrocarbons, (PAHs) certain volatile organic compounds, and arsenic are other potential mutagens. Some forms of radiation, such as Potassium-40 and various isotopes of radium have been identified as potential mutagens as well (Seiler RL).

By using leukemia clusters, researchers have been able to identify railroads, petrochemical plants, nuclear power plants, gas stations, and roads with high traffic densities as potential sources of these mutagenic agents inducing higher rates of leukemia. The closer the proximity of the individual to the source, the greater the risk of developing the malignancy.

The Myth of Electromagnetic Fields and Leukemia

There has been a wide variety of studies that have sought to answer the question of whether or not an electromagnetic field induced by a power line can lead to increased risk in developing leukemia, as well as other cancers, particularly neurological cancers. The results have been conflicting so far. Studies that do allude to a potential correlation between proximity to a power line and leukemia risk have produced underwhelming results (Draper G, Vincent T, Kroll M). It is possible that there is a link between a child living close to a power line and a child living in a worse socioeconomical living situation as compared to a child not living near a power line (Draper G, Vincent T, Kroll M). With disparities in diets and healthcare between social classes, its possible that these power line associated correlations are a side result of a larger scheme.

Prognosis and treatment

Prognosis and treatment differ according to the type of leukemia. Treatment of leukemia must be tailored to the type of leukemia and individual patient characteristics. For example, while CLL is an incurable disease with standard chemotherapy, patients may require no treatment (ie. "watchful waiting") for years if they are asymptomatic. In contrast, some patients with AML will die within hours or days of presentation unless intensive combination chemotherapy regimen is given and in some cases will require allogeneic stem cell transplant. This type of regimen would not be suited for an elderly patient or one with significant comorbid conditions.

Current research is directed at targeting the molecular mechanisms of the leukemia. One of the recent successes in targeted therapy is imatinib (Gleevec, Glivec). Imatinib inhibits the Abl tyrosine kinase which is constitutively activated by the bcr/abl translocation found in patients with CML and some patients with ALL.

External links

• FAQ on leukemia
• Information and advocacy for leukemia
• Leukaemia Research Fund (UK)
• The Anthony Nolan Trust (UK)
• Unofficial summary of UKCCS, and of UKCCS publications
• Association of Cancer Online Resource (ACOR) Leukemia Links

{{Diseases of RBCs and megakaryocytes}} may refer to:

• {{Diseases of RBCs}}, a navigational template for diseases of red blood cells
• {{Diseases of megakaryocytes}}, a navigational template for diseases of clotting

References

Agha M, Williams JI, et al. Congenital abnormalities and childhood cancer. American Cancer Society. 103(9), 2005.

Capalbo S, Callea V, et al. Familial B-cell chronic lymphocytic leukemia in a population of patients from Southern Italy. International Journal of Hematology. 79(4), 2004.

Draper G, Vincent T, Kroll M. Childhood cancer in relation to distance from high voltage power lines in England and Wales: a case-control study. British Medical Journal. 330:1290, June.

Gilham C, Peto J, et al. Day care in infancy and risk of childhood acute lymphoblastic leukemia: findings from UK case-control study. British Medical Journal. Doi: 10.1136/bmj.38428.521042.8F. 2005.

Infante-Rivard C and Guiguet M. Family history of hematopoietic and other cancers in children with acute lymphoblastic leukemia. International Society for Preventive Oncology. 28(2), 2004.

Kwan ML, Block G, et al. Food consumption by children and the risk of childhood acute leukemia. American Journal of Epidemiology. 160(11), 2004.

Patja K, Pukkala E, et al. Cancer incidence of persons with Down syndrome in Finland: A population-based study. International Journal of Cancer. 2005.

Perrillat F, Clavel K, et al. Family cancer history and risk of childhood acute leukemia. Cancer Causes and Control. 12, 2001.

Perillat-Menegaux F, Clavel J, et al. Family history of autoimmune thyroid disease and childhood acute leukemia. American Association for Cancer Research: Cancer Epidemiology Biomarkers and Prevention. 12, 2003.

Praghakaran K, Wise B, et al. Rational management of lymphoproliferative disorder in pediatric patients. Journal of Pediatric Surgery. 34(1), 1999.

Seiler RL. Temporal changes in water quality at a childhood leukemia cluster. Ground Water. 42(3), 2004.

Steffen C, Auclerc MF, et al. Acute childhood leukemia and environmental exposure to potential sources of benzene and other hydrocarbons; a case-control study. Occupational and Environmental Medicine. 61, 2004.

Wechsler J, Greene M, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nature Genetics. 32, 2002.