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Lymphoid Leukemias

Moshe E. Gatt, Shai Izraeli

Leukemias are a group of hematological malignant clonal diseases promoted the hypothesis that at least two genetic hits are required
2
arising in bone marrow. This chapter focuses on the two most for the development of ALL (Fig. 78.1). The first occurs during
common lymphoid leukemias: acute lymphoblastic leukemia fetal lymphopoiesis, most likely because of a “developmental
(ALL) and chronic lymphocytic leukemia (CLL). The immuno- accident” of the V(D)J recombination machinery, and results
logical aspects of both diseases are extensively discussed, with a in clonal proliferation of a preleukemic clone. Intrauterine
special emphasis on the clinical and laboratory features of each metastasis of this clone from one twin to the other via their
disorder. shared placental circulation is responsible for the concordant
leukemia. Additional genetic hits in the preleukemic cells occur
ACUTE LYMPHOBLASTIC LEUKEMIA after birth and are required for the development of full-blown
leukemia. The initial findings in identical twins with leukemia
ALL manifests with the clonal proliferation and accumulation have been extended to sporadic ALL. In at least 70% of the
of malignant lymphoid progenitors. ALL is a developmental patients, the preleukemic clone can be detected molecularly
disease. Most childhood ALLs arise as a “developmental accident” in the neonatal blood samples collected after birth (known
during normal fetal lymphopoiesis. Studies of chromosomal as Guthrie cards). More recently, careful molecular analysis of
translocations in ALL cells have identified key genes involved in the cord blood of normal infants has demonstrated that the
normal lymphopoiesis and hematopoiesis. Conversely, basic occurrence of a preleukemic clone carrying a leukemia-defining
studies of the development of the immune system and the immune chromosomal translocation might be common. However, only
receptors have provided important tools for the diagnosis and 1% of children born with such a preleukemic clone will develop
management of ALL. These achievements in basic and clinical leukemia, implying the impracticality of molecular screen for
research have led to the remarkable transformation of ALL from early diagnosis of childhood ALL.
a uniformly fatal disorder to a disease that is curable in more
1
than 80% of children. Adults, however, have not fared as well.
KEY CONCEPTS
Epidemiology and Etiology Environmental Factors in the Epidemiology of
ALL is the most common malignancy of childhood. One of Childhood Acute Lymphoblastic Leukemia (ALL):
every 2000 children will develop leukemia by 15 years of age. Roles for Infection and Immunity?
In contrast, ALL accounts for <20% of leukemias in adults. In
developed countries, incidence peaks at 2–5 years of age. This “Common” B-cell precursor ALL at the preschool age is the most common
low age at peak of incidence is characteristic of affluent societies. 2 type of ALL in the suburban regions of affluent countries. The causes
for this phenomenon are unknown. A popular hypothesis suggests a
Most ALLs are sporadic. Less than 5% are associated with modified immune response to delayed infections during infancy.
hereditary or constitutional syndromes. Children with Down
syndrome have an approximately 20-fold increased risk of
developing ALL. Other diseases associated with increased risk The causes of the relatively rare postnatal leukemogenic genetic
include inherited genomic instability syndromes, such as ataxia– hits are unknown. As the risk of B-cell precursor ALL during
telangiectasia, Bloom syndrome, and Li-Fraumeni syndrome. early childhood is markedly increased by higher socioeconomic
Conversely, ALL is more common in patients with congenital status and a suburban style of living in which the exposure of
B-cell immune deficiencies (Chapter 34). These include X-linked children to infectious pathogens is typically delayed beyond the
agammaglobulinemia (XLA), selective immunoglobulin A (IgA) neonatal period, Greaves hypothesized that many childhood cases
deficiency, and common variable immunodeficiency (CVID). are the consequence of an abnormally late immunological
2
Interestingly, some cases of CVID associated with leukemia have response to common infections. One proposed mechanism is
been recently shown to be caused by germline mutations in that growth inhibitory factors, such as interferon (IFN) or
3
IKZF1, which encodes the lymphoid transcription factor Ikaros. transforming growth factor-β (TGF-β), secreted during this
Germline mutations in additional hematopoietic and B-cell immune response provide a survival advantage to a preleukemic
6
5
4
developmental genes, such as ETV6, , RUNX1, and PAX5, also clone setting the stage for additional leukemogenic mutations.
predispose to ALL. Recently a more direct suggestion for the involvement of infection
Although ALL is not hereditary, there is a markedly increased (or the response to infection) in the pathogenesis of ALL has
risk of leukemias in identical twins, and studies in these twins have been provided. Pax5 heterozygous mice developed preB-cell ALL
shed light on the etiology of childhood ALL. This phenomenon has only after exposure to common mouse pathogens. 7
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