Etiology And Pathogenesis

ALL occurs more frequently in boys and Caucasian children. The incidence peaks at 2 to 5 years, as shown in Figure 55-2. AML affects boys and girls equally, and pediatric incidence peaks in the neonatal and late adolescent periods (see Figure 55-2). In the United States, Hispanic and African American children are diagnosed with AML slightly more often than Caucasian children.

Figure 55-2 Incidence rates of acute lymphoblastic leukemia and acute myelogenous leukemia.

Leukemic cells are derived from hematopoietic stem cells that acquire genetic alterations that affect their ability to mature or undergo apoptosis, leading to perpetual self-renewal. The etiology of most of these mutations is unknown; however, certain environmental exposures, familial factors, genetic syndromes, and infectious diseases have been investigated as predisposing agents in childhood leukemia.

Studies of twins, neonatal blood spots (Guthrie cards), and cord blood are beginning to provide insight into the development of acute leukemia. In twin studies, concordance for all leukemias in monozygotic pairs is 5% to 25%; 10% in ALL and approaching 100% in infant leukemia. The extraordinarily high twin concordance rate for infant leukemia is attributed to blood chimerism of monochorionic twins. It is thought that the leukemia cells are passed from one twin to the other via a shared blood supply. This chimerism also occurs through placental vascular anastomoses in approximately 8% of dichorionic twin pairs.

Upon review of Guthrie cards of children who later developed leukemia, genetic mutations unique to leukemic clones were found to be present at birth, suggesting some leukemia may originate in utero. Because not all children with these mutations at birth develop leukemia, the mutations are believed to be necessary but not sufficient to induce leukemogenesis. Clearly, a second mutation and probably multiple sequences of mutations are required. Based on twin concordance studies, these latter mutations most likely occur postnatally.

Prenatal and postnatal genetic insults resulting in leukemia can be extrapolated to nontwin patients. A survey of hundreds of cord blood samples revealed that 1% had a functional TEL-AML1 gene (a common chromosomal translocation in pre B-cell ALL). This rate is 100 times that of clinically diagnosed ALL in the pediatric population. This serves as additional evidence that the genetic abnormalities found in cord blood at birth are not sufficient alone to result in the development of ALL.

Several environmental factors are associated with pediatric leukemia. These include ionizing radiation and chemotherapeutic agents, such as topoisomerase II inhibitors and alkylating agents. Other suspected environmental exposures include hydrocarbons such as benzene and pesticides leading to AML. Children with inherited genetic syndromes, including trisomy 21, Fanconi anemia, ataxia-telangiectasia, Wiskott-Aldrich syndrome, and neurofibromatosis type I, have an increased risk of developing acute leukemia.

Infectious agents have been proposed as playing a role in the development of leukemia, especially ALL. The peak age of incidence correlates with the age of first exposure to many infections for children in developed countries. Additionally, pediatric leukemia is more common in industrial regions of developed countries than in developing countries. It is thought that the later onset of exposure to infectious agents seen in developed countries results in an abnormally rapid immune cell proliferation and dysregulation. This hypothesis is also supported by several studies that compared infectious exposures of children who did and did not attend daycare early in life. The results showed that children with early daycare attendance and earlier exposure to infectious agents were less likely to develop ALL.

Genetics

Although little is known about the cause of initial mutations in the hematopoietic stem cell DNA of leukemia cells, the resultant genetic abnormalities are well studied. Leukemia is caused by multiple disruptions in cell DNA leading to (1) impaired maturation, (2) unregulated proliferation, and (3) lack of programmed cell death (apoptosis). In combination, this leads to the abnormal survival of mutated hematopoietic progenitor cells and unregulated growth of dysfunctional lymphoblasts or myeloblasts.

Some of the mutations are caused by chromosomal translocations resulting in fusion proteins that bring activated kinases and altered transcription factors together inappropriately. TEL-AML1 is the most commonly identified chromosomal translocation in pediatric ALL. TEL-AML1 t(8;21) is the product of the TEL gene responsible for recruiting progenitor stem cells into the bone marrow and the AML1 gene that plays a central role in hematopoietic cell differentiation. The Philadelphia chromosome is the product of a translocation of chromosomes 9 and 22, which is found in 95% of patients with CML and 2% of those with ALL. The translocation results in a fusion protein, BCR-ABL, which encodes a constitutively active tyrosine kinase protein. The tyrosine kinase activates proteins responsible for signaling within the cell cycle, therefore inducing uncontrolled cell proliferation, reducing apoptosis, and inhibiting DNA repair mechanisms (Figure 55-3). MLL, found on chromosome 11q23, partners with more than 40 genes and is found in childhood AML, secondary (or therapy-induced) AML, and the majority of infant ALL. Because the MLL gene arrangement is associated with several types of leukemia, specifically secondary AML after prior topoisomerase II inhibitor exposure, investigators are evaluating environmental topoisomerase II exposures that might be responsible for in utero mutations resulting in infant leukemia.

Figure 55-3 Genetics of acute lymphoblastic leukemia and acute myelogenous leukemia.

The process of cytogenetic profiling involves evaluating leukemic blasts for both the number of chromosomes and specific translocations (see Figure 55-3). This information is used to classify leukemia subtypes and give prognostic information and is often part of treatment risk stratification algorithms. For example, in pre–B-cell ALL, hyperdiploidy (>50 chromosomes) is associated with a good prognosis. However, hypodiploidy (<45 chromosomes) signifies a poor prognosis. Patients with AML are considered to have good-risk disease if the leukemia cell contains t(8;21) and inv(16) mutations. Other genetic abnormalities such as monosomy 5 and 7 and abnormalities of 3q are considered unfavorable. As many as 40% of patients with AML have activating mutations within the FLT3 gene, which are known as internal tandem duplications (ITDs). Both increased number of ITDs and location within the FLT3 gene are associated with poor clinical outcome.