acute lymphoblastic leukemia acute lymphoblastic leukemia acute lymphoblastic leukemia (all) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain. as an acute leukemia, all progresses rapidly and is typically fatal within weeks or months if left untreated. acute lymphoblastic leukemiaother namesacute lymphocytic leukemia, acute lymphoid leukemiabone marrow aspirate smear from a person with precursor b-cell all. the large purple cells are lymphoblasts.specialtyhematology, oncologysymptomsfeeling tired, pale color, fever, easy bleeding or bruising, bone pain, enlarged lymph nodescomplicationsinfection, tumor lysis syndromeusual onset2–5 years oldtypesb-cell all, t-cell allcausesusually unknownrisk factorsidentical twin with all, down syndrome, fanconi anemia, ataxia telangiectasia, klinefelter syndrome, high birth weight, significant radiation exposurediagnostic methodblood tests and bone marrow examinationdifferential diagnosisinfectious mononucleosis, acute myeloid leukemia, lymphoblastic lymphoma, aplastic anemiatreatmentchemotherapy, stem cell transplantation, radiation therapy, targeted therapyprognosischildren: 90% five-year survival rateadults: 35% five-year survivalfrequency1 in 1,750 childrendeaths111,000 (2015) in most cases, the cause is unknown. genetic risk factors may include down syndrome, li–fraumeni syndrome, or neurofibromatosis type 1. environmental risk factors may include significant radiation exposure or prior chemotherapy. evidence regarding electromagnetic fields or pesticides is unclear. some hypothesize that an abnormal immune response to a common infection may be a trigger. the underlying mechanism involves multiple genetic mutations that results in rapid cell division. the excessive immature lymphocytes in the bone marrow interfere with the production of new red blood cells, white blood cells, and platelets. diagnosis is typically based on blood tests and bone marrow examination. all is typically treated initially with chemotherapy aimed at bringing about remission. this is then followed by further chemotherapy typically over a number of years. treatment usually also includes intrathecal chemotherapy since systemic chemotherapy can have limited penetration into the central nervous system and the central nervous system is a common site for relapse of acute lymphoblastic leukemia. treatment can also include radiation therapy if spread to the brain has occurred. stem cell transplantation may be used if the disease recurs following standard treatment. additional treatments such as chimeric antigen receptor t cell immunotherapy are being used and further studied. all affected about 876,000 people globally in 2015 and resulted in about 111,000 deaths. it occurs most commonly in children, particularly those between the ages of two and five. in the united states it is the most common cause of cancer and death from cancer among children. all is notable for being the first disseminated cancer to be cured. survival for children increased from under 10% in the 1960s to 90% in 2015. survival rates remain lower for babies (50%) and adults (35%). signs and symptoms initial symptoms can be nonspecific, particularly in children. over 50% of children with leukemia had one or more of five features: a liver one can feel (64%), a spleen one can feel (61%), pale complexion (54%), fever (53%), and bruising (52%). additionally, recurrent infections, feeling tired, arm or leg pain, and enlarged lymph nodes can be prominent features. the b symptoms, such as fever, night sweats, and weight loss, are often present as well. central nervous system (cns) symptoms such as cranial neuropathies due to meningeal infiltration are identified in less than 10% of adults and less than 5% of children, particularly mature b-cell all (burkitt leukemia) at presentation. the signs and symptoms of all are variable and include: generalized weakness and feeling tired anemia dizziness headache, vomiting, lethargy, neck stiffness, or cranial nerve palsies (cns involvement) frequent or unexplained fever and infection weight loss and/or loss of appetite excessive and unexplained bruising bone pain, joint pain (caused by the spread of "blast" cells to the surface of the bone or into the joint from the marrow cavity) breathlessness enlarged lymph nodes, liver, and/or spleen pitting edema (swelling) in the lower limbs and/or abdomen petechiae, which are tiny red spots or lines in the skin due to low platelet levels testicular enlargement mediastinal mass cause in all, lymphoid cell development stops at the lymphoblast (arrow), which are also overproduced. the cancerous cell in all is the lymphoblast. normal lymphoblasts develop into mature, infection-fighting b-cells or t-cells, also called lymphocytes. signals in the body control the number of lymphocytes so neither too few nor too many are made. in all, both the normal development of some lymphocytes and the control over the number of lymphoid cells become defective. all emerges when a single lymphoblast gains many mutations to genes that affect blood cell development and proliferation. in childhood all, this process begins at conception with the inheritance of some of these genes. these genes, in turn, increase the risk that more mutations will occur in developing lymphoid cells. certain genetic syndromes, like down syndrome, have the same effect. environmental risk factors are also needed to help create enough genetic mutations to cause disease. evidence for the role of the environment is seen in childhood all among twins, where only 10–15% of both genetically identical twins get all. since they have the same genes, different environmental exposures explain why one twin gets all and the other does not. infant all is a rare variant that occurs in babies less than one year old. kmt2a (formerly mll) gene rearrangements are most common and occur in the embryo or fetus before birth. these rearrangements result in increased expression of blood cell development genes by promoting gene transcription and through epigenetic changes. in contrast to childhood all, environmental factors are not thought to play a significant role. aside from the kmt2a rearrangement, only one extra mutation is typically found. environmental exposures are not needed to help create more mutations. genetics common inherited risk factors include mutations in arid5b, cdkn2a/2b, cebpe, ikzf1, gata3, pip4k2a and, more rarely, tp53. these genes play important roles in cellular development, proliferation, and differentiation. individually, most of these mutations are low risk for all. significant risk of disease occurs when a person inherits several of these mutations together. the uneven distribution of genetic risk factors may help explain differences in disease rates among ethnic groups. for instance, the arid5b mutation is less common in ethnic african populations. several genetic syndrome also carry increased risk of all. these include: down syndrome, fanconi anemia, bloom syndrome, x-linked agammaglobulinemia, severe combined immunodeficiency, shwachman–diamond syndrome, kostmann syndrome, neurofibromatosis type 1, ataxia-telangiectasia, paroxysmal nocturnal hemoglobinuria, and li–fraumeni syndrome. fewer than 5% of cases are associated with a known genetic syndrome. rare mutations in etv6 and pax5 are associated with a familial form of all with autosomal dominant patterns of inheritance. environmental the environmental exposures that contribute to emergence of all is contentious and a subject of ongoing debate. high levels of radiation exposure from nuclear fallout is a known risk factor for developing leukemia. evidence whether lesser radiation, as from x-ray imaging during pregnancy, increases risk of disease remains inconclusive. studies that have identified an association between x-ray imaging during pregnancy and all found only a slightly increased risk. exposure to strong electromagnetic radiation from power lines has also been associated with a slightly increased risk of all. this result is questioned as no causal mechanism linking electromagnetic radiation with cancer is known. high birth weight (greater than 4000 g or 8.8 lbs) is also associated with a small increased risk. the mechanism connecting high birth weight to all is also not known. evidence suggests that secondary leukemia can develop in individuals treated with certain types of chemotherapy, such as epipodophyllotoxins and cyclophosphamide. infections there is some evidence that a common infection, such as influenza, may indirectly promote the emergence of all. the delayed-infection hypothesis states that all results from an abnormal immune response to infection in a person with genetic risk factors. delayed development of the immune system due to limited disease exposure may result in excessive production of lymphocytes and increased mutation rate during an illness. several studies have identified lower rates of all among children with greater exposure to illness early in life. very young children who attend daycare have lower rates of all. evidence from many other studies looking at disease exposure and all is inconclusive. some researchers have linked the hygiene hypothesis. mechanism several characteristic genetic changes lead to the creation of a leukemic lymphoblast. these changes include chromosomal translocations, intrachromosomal rearrangements, changes in the number of chromosomes in leukemic cells, and additional mutations in individual genes. chromosomal translocations involve moving a large region of dna from one chromosome to another. this move can result in placing a gene from one chromosome that promotes cell division to a more actively transcribed area on another chromosome. the result is a cell that divides more often. an example of this includes the translocation of c-myc, a gene that encodes a transcription factor that leads to increased cell division, next to the immunoglobulin heavy- or light-chain gene enhancers, leading to increased c-myc expression and increased cell division. other large changes in chromosomal structure can result in the placement of two genes directly next to each other. the result is the combination of two usually separate proteins into a new fusion protein. this protein can have a new function that promotes the development of cancer. examples of this include the etv6–runx1 fusion gene that combines two factors that promote blood cell development and the bcr-abl1 fusion gene of the philadelphia chromosome. bcr–abl1 encodes an always-activated tyrosine kinase that causes frequent cell division. these mutations produce a cell that divides more often, even in the absence of growth factors. other genetic changes in b-cell all include changes to the number of chromosomes within the leukemic cells. gaining at least five additional chromosomes, called high hyperdiploidy, occurs more commonly. less often, chromosomes are lost, called hypodiploidy, which is associated with a poorer prognosis. additional common genetic changes in b-cell all involve non-inherited mutations to pax5 and ikzf1. in t-cell all, lyl1, tal1, tlx1, and tlx3 rearrangements can occur. all results when enough of these genetic changes are present in a single lymphoblast. in childhood all, for example, one fusion gene translocation is often found along with six to eight other all-related genetic changes. the initial leukemic lymphoblast copies itself into an excessive number of new lymphoblasts, none of which can develop into functioning lymphocytes. these lymphoblasts build up in the bone marrow and may spread to other sites in the body, such as lymph nodes, the mediastinum, the spleen, the testicles, and the brain, leading to the common symptoms of the disease. diagnosis diagnosing all begins with a thorough medical history, physical examination, complete blood count, and blood smears. while many symptoms of all can be found in common illnesses, persistent or unexplained symptoms raise suspicion of cancer. because many features on the medical history and exam are not specific to all, further testing is often needed. a large number of white blood cells and lymphoblasts in the circulating blood can be suspicious for all because they indicate a rapid production of lymphoid cells in the marrow. the higher these numbers typically point to a worse prognosis. while white blood cell counts at initial presentation can vary significantly, circulating lymphoblast cells are seen on peripheral blood smears in the majority of cases. a bone marrow biopsy provides conclusive proof of all, typically with >20% of all cells being leukemic lymphoblasts. a lumbar puncture (also known as a spinal tap) can determine whether the spinal column and brain have been invaded. brain and spinal column involvement can be diagnosed either through confirmation of leukemic cells in the lumbar puncture or through clinical signs of cns leukemia as described above. laboratory tests that might show abnormalities include blood count, kidney function, electrolyte, and liver enzyme tests. pathological examination, cytogenetics (in particular the presence of philadelphia chromosome), and immunophenotyping establish whether the leukemic cells are myeloblastic (neutrophils, eosinophils, or basophils) or lymphoblastic (b lymphocytes or t lymphocytes). cytogenetic testing on the marrow samples can help classify disease and predict how aggressive the disease course will be. different mutations have been associated with shorter or longer survival. immunohistochemical testing may reveal tdt or calla antigens on the surface of leukemic cells. tdt is a protein expressed early in the development of pre-t and pre-b cells, whereas calla is an antigen found in 80% of all cases