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182 Part IV: Molecular and Cellular Hematology Chapter 13: Cytogenetics and Genetic Abnormalities 183

RPS14 gene, cooperate with loss of RPS14 and mediate the megakary- kinase activity (BCR-ABL1 p190 ). Genetic alterations of the IKZF1 gene
ocytic dysplasia seen in this disease. These studies raise the possibility are detectable in up to 80 percent of patients with Ph chromosome–pos-
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that haploinsufficiency for one or more of these genes in hematopoietic itive ALL, and are associated with an unfavorable outcome even with
stem cells (HSCs) may contribute to the pathogenesis of MDS or AML the use of TKIs. 66
with a del(5q), and a study demonstrated that haploinsufficiency for two
del(5q) genes, EGR1 and APC, together with loss of TP53 leads to AML
in a mouse model. 62 Translocations Involving 11q
A second subtype of t-AML has been identified that is distinctly Translocations involving the KMT2A gene at 11q23.3 are observed in
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different from the more common leukemia that follows alkylating 5 percent of ALL patients. Of these, the most common is the t(4;11)
agents or irradiation. This type of t-AML is seen in patients receiving (q21.3;q23.3) (Fig. 13–5). The t(11;19)(q23.3;p13.3) is second in fre-
drugs known to inhibit topoisomerase II, for example, etoposide, teni- quency. However, this rearrangement is not limited to ALL in that
poside, and doxorubicin. Clinically, these patients have a shorter latency approximately 50 percent of these cases have AML, usually monoblas-
period (1 to 2 years), present with overt leukemia, often with monocytic tic. Of note is the high frequency of translocations involving 11q23.3
features, without a preceding myelodysplastic phase, and have a more in infant ALL (60 to 80 percent). Patients with the t(4;11) have a pro
favorable response to intensive induction therapy. Balanced transloca- B-cell phenotype (CD10−, CD19+), with coexpression of monocytic
tions involving the KMT2A gene at 11q23.3, or the RUNX1/AML1 gene (CD15+), or, less commonly, T-cell markers. Clinically, both children
at 21q22.3 are common in this subgroup. 54 and adults have aggressive features with hyperleukocytosis, extramed-
ullary disease, and a poor response to conventional chemotherapy.
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Adults with the t(4;11) have a remission rate of 75 percent, but a median
ACUTE LYMPHOBLASTIC LEUKEMIA EFS of only 7 months. Rearrangements affecting KMT2A represent a
ALL is the most frequent leukemia in children (Chap. 91). In both major class of mutations in acute leukemia and identify patients with a
childhood and adult ALL, the identification of prognostic subgroups poor outcome.
based on recurring cytogenetic abnormalities (Table 13–4) and molec-
ular markers has resulted in the application of risk-adapted therapies.
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The most useful prognostic indicators are karyotype (including ploidy), Translocation 12;21
age, white blood cell count, and response to initial therapy (day 14 mar- The t(12;21)(p13.2;q22.3) has been identified in a high proportion
row response and end-induction minimal residual disease). Based on (approximately 25 percent) of childhood precursor B-cell leukemia, but
these parameters, the Children’s Oncology Group has defined four risk is uncommon in adults (approximately 5 percent of ALL cases) (Fig.
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groups: lower risk (5-year event-free survival [EFS], at least 85 percent), 13–6). The translocation is not easily detected by cytogenetic anal-
with either the ETV6/RUNX1 fusion, or simultaneous trisomies of chro- ysis because of the similarity in size and banding pattern of 12p and
mosomes 4, 10, and 17; standard and high risk (those remaining in the 21q. However, the rearrangement can be detected reliably using reverse
respective National Cancer Institute risk groups); and very high risk transcriptase polymerase chain reaction (RT-PCR) or FISH analysis.
(5-year EFS, 45 percent or below), with extreme hypodiploidy (fewer The t(12;21) defines a distinct subgroup of patients characterized by an
than 44 chromosomes), or the BCR-ABL1 fusion, and induction fail- age between 1 and 10 years, B-cell lineage immunophenotype (CD10+,
ure. Genome-wide profiling studies using CMA revealed a high fre- CD19+, HLA-DR+), and a favorable outcome, particularly when other
64
quency of submicroscopic copy-number abnormalities in pediatric ALL, favorable risk factors are present. In one study, patients with the t(12;21)
including deletions of PAX5 (32 percent), IKZF1 (IKAROS, 29 percent), had a 5-year EFS of 91 percent as compared to 65 percent for patients
CDKN2A/B (50 percent), BTG1, and EBF1 (8 percent). Many of these without this rearrangement. However, the t(12;21) may be associated
abnormalities disrupt genes and pathways controlling B-cell develop- with late disease recurrences. The t(12;21) results in a fusion protein
ment and differentiation, and the most clinically significant among containing the N-terminus of ETV6/TEL, a transcriptional repres-
them appears to be genetic alterations of IKZF1, which are invariably sor of the ETS family, and most of the RUNX1/AML1 transcription
associated with a very poor outcome in B-cell progenitor ALL. 9 factor.

Translocation 9;22 Hyperdiploidy
The incidence of the t(9;22) in ALL is 30 percent in adults (the inci- The leukemia cells of some patients with ALL are characterized by a
dence may approach 50 percent in adults older than 60 years of age) and gain of many chromosomes (see Fig. 13–6). Two distinct subgroups are
5 percent in children. Thus, the Ph chromosome is the most frequent recognized: a group with 1 to 4 extra chromosomes (47 to 50), and the
rearrangement in adult ALL. Approximately 70 percent of the patients more common group with more than 50 chromosomes. Chromosome
show additional abnormalities, a frequency that is substantially higher numbers usually range from 51 to 60, and a few patients may have up to
than that observed in CML with +der(22)t(9;22),+21, abnormalities 65 chromosomes. Hyperdiploidy (>50 and usually <66 chromosomes) is
of 9p, +8, −7, and +X (noted in descending frequency). Monosomy 7 common in children (approximately 30 percent), but is rarely observed
is associated with a poorer outcome. A chromosomally normal cell in adults (<5 percent). Certain additional chromosomes are com-
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line is frequently noted in the marrow of Ph chromosome-positive ALL mon (X chromosome, and chromosomes 4, 6, 10, 14, 17, 18, and 21).
patients (70 percent), but is rare in untreated CML. Most cases have a Chromosome 21 is gained most frequently (100 percent of cases).
B-lineage phenotype (CD10+, CD19+, and TdT+), but there is frequent Patients who have hyperdiploidy with more than 50 chromosomes have
expression of myeloid-associated antigens (CD13 and CD33). The dis- all of the previously recognized clinical factors that indicate a good
ease in both adults and children is characterized by high white blood prognosis, including age between 1 and 9 years, low white blood cell
cell counts, a high percentage of circulating blasts, and a poor prognosis. count (median 6700/μL), and favorable immunophenotype (early pre-B
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As in CML, the t(9;22) in ALL results in a BCR-ABL1 fusion gene. How- cell or pre-B cell). The favorable prognosis associated with high hyper-
ever, in more than half of the patients, the break in BCR is more prox- diploidy is associated with gains of chromosomes 4, 10, and 17, whereas
imal, resulting in a smaller fusion protein with even greater tyrosine a gain of chromosomes 5 and i(17q) is associated with a poor outcome. 69

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