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C H A P T E R 64

PATHOBIOLOGY OF ACUTE LYMPHOBLASTIC LEUKEMIA

Melissa Burns, Scott A. Armstrong, and Alejandro Gutierrez

Normal lymphoid precursors undergo somatic recombination at their the blast cell phenotypes differ from those of normal lymphocyte
1
immunoglobulin (Ig) or T- cell receptor (TCR) gene loci, and the progenitors, which is likely a result of aberrant regulation of gene
successful completion of V(D)J recombination, with the resultant expression. Still the general concept that leukemic cells should be
formation of a functional Ig or TCR, is required for the survival of classified according to their “normal” developmental stage remains an
lymphocyte precursors. Positive and negative selection steps ensure important one, providing a basis for the study of immunophenotype-
that only lymphocytes with Ig or TCRs that function appropriately specific genetic changes.
within the context of an individual’s immune microenvironment are
allowed to proceed through the proliferation and differentiation steps
required for the development of mature lymphocytes. This develop- Mature B-Cell Acute Lymphoblastic Leukemia
mental process generates a repertoire of mature lymphocytes with
unique variations in the antigen-recognition portions of the Ig or The diagnosis of mature B-cell ALL, also termed Burkitt leukemia, is
TCR genes; together these form the foundation of the adaptive based on the detection of surface Ig on leukemic blasts. This rare
immune system that can recognize a countless variety of foreign phenotype accounts for only 2%–3% of ALL cases, and the lympho-
antigens. The acquisition of mutations of oncogenes or tumor sup- blasts generally have distinctive morphology, with deeply basophilic
pressors during this developmental process, which can be mediated cytoplasm containing prominent vacuoles; this morphologic pattern
2,3
by off-target activity of the V(D)J recombination machinery, can is designated L3 in the French-American-British (FAB) system. 14–16
lead to the dysregulated proliferation and differentiation arrest that Mature B-cell ALL is a disseminated form of Burkitt lymphoma, as
are characteristic of acute lymphoblastic leukemia (ALL). Many of these conditions share common cytogenetic, molecular, phenotypic,
17
these genetic alterations have prognostic significance and are used in and clinical features. Mature B-cell ALL does not respond well to
modern ALL treatment protocols to adjust the intensity of therapy. chemotherapy traditionally used for childhood ALL. However, good
Although the incidence of specific genetic alterations in ALL varies outcomes have been obtained with treatments designed for Burkitt
according to patient age (Fig. 64.1), evidence suggests that the lymphoma, which involve relatively brief but intensive regimens that
pathogenesis underlying malignant transformation in molecularly emphasize cyclophosphamide and the rapid rotation of antimetabo-
defined subsets of ALL is similar across age groups. 4,5 lites in high dosages. 18–22 Thus, mature B-cell leukemia was the first
form of ALL to be recognized as a distinct clinical entity based on
immunophenotypic and cytogenetic features, and the first to be
CLONAL ORIGIN OF LEUKEMIC LYMPHOID CELLS treated by separate protocols designed specifically for the leukemia’s
unique features.
The clonal origin of leukemia was first suggested by the identification
of the Philadelphia (Ph) chromosome in chronic myeloid leukemia
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(CML). Subsequently, numerous lines of evidence have provided Precursor B-Cell Acute Lymphoblastic Leukemia
additional support for this theory, which is now generally accepted.
Uniform structural and numerical chromosomal abnormalities are Approximately 80% of ALL patients have lymphoblasts with pheno-
frequently demonstrated in all leukemic lymphoblasts from an types corresponding to those of B-cell progenitors. 16,23 These cases
individual patient. Identical rearrangements of Ig or TCR genes, can be identified on the basis of cell surface expression of CD19 and
which are somatic in origin, have been demonstrated in ALL cell at least one other recognized B lineage-associated antigen: CD20,
7,8
populations. Additionally, identical patterns of X-chromosome CD24, CD22, CD21, or CD79. 16,23 The most common subtype of
inactivation have been demonstrated within all cells of individual precursor B-cell ALL, termed common precursor B-cell ALL, also
patients with ALL by allelic analysis of the glucose-6-phosphate expresses CD10. These lymphoblasts may also express nuclear termi-
9
dehydrogenase gene on the X chromosome. Moreover, the methyla- nal deoxynucleotidyl transferase (TdT) or CD34. About one-fourth
tion patterns of restriction fragment length polymorphisms in of precursor B-cell ALL cases express cytoplasmic Ig µ heavy-chain
X-linked genes, as detected by Southern blot analysis, have been used proteins and are designated pre-B ALL.
to show that even rare ALL cases with two completely different DNA rearrangement of Ig genes occurs before heavy-chain gene
cytogenetic clones probably arise by clonal evolution from a single expression in B-cell development, providing a genetic marker of
transformed progenitor. 10 B-lymphocyte ontogeny. Korsmeyer and coworkers pioneered the use
of heavy- and light-chain gene rearrangements to support an early
24,25
LINEAGE-SPECIFIC FEATURES OF LEUKEMIC B-lineage origin of most ALL blasts. However, Ig heavy-chain
gene rearrangements have also been documented in about 15% of
LYMPHOBLASTS T-cell ALL cases and in a similar percentage of acute myeloid leuke-
mia (AML) cases. 26–28 Thus, caution must be exercised when assigning
Malignant lymphoblasts share many of the features of normal lym- cell lineage on the basis of studies of Ig gene rearrangement.
phoid progenitors. 11,12 Thus, ALL cells rearrange their Ig and TCR The identification of specific immunophenotypic, genetic, and
genes and express components of antigen receptor molecules and clinical features that predict response to therapy in patients with
other differentiation-linked cell-surface glycoproteins in ways that B-lineage ALL, and the incorporation of these predictors into clinical
correspond to features of developing normal B and T lymphocytes. decision making, are now widespread in modern ALL treatment
In many cases, leukemic cells appear to represent the clonal expansion protocols. This ability to predict outcome has been closely tied to the
of a lymphoid progenitor that has arrested its development at an early remarkable improvements in therapy for children with this disease,
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stage of B- or T-cell differentiation. However, in many cases of ALL, which 50 years ago was universally fatal. However, many subgroups
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