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180 Part IV: Molecular and Cellular Hematology Chapter 13: Cytogenetics and Genetic Abnormalities 181

these as a distinct form of AML (Chap. 88). These aberrations are rel- KMT2A exons 2 to 6 or 2 to 8 mediated by recombination between Alu
atively common, occurring in 5 percent of AML and 25 percent of repetitive elements and may produce a partially duplicated protein.
AMML patients. These patients have a good response to intensive
1
chemotherapy with a complete remission rate of approximately 90 per- Inversion 3 and t(3;3)
33
cent and an overall 5-year survival of 60 percent. The breakpoint at Each of the other recurring rearrangements in AML occurs in fewer than
16q22 occurs within the CBFB gene, which encodes one subunit of the 3 percent of patients. A unique feature of abnormalities involving the
RUNX1/CBFB transcription factor. Thus, like the t(8;21), the inv(16) long arm of chromosome 3 [inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)]
disrupts the RUNX1/AML1 pathway regulating hematopoiesis. Second- is the presence of platelet counts greater than 100 × 10 /L, sometimes
9
ary cooperating mutations of KIT, KRAS, and NRAS are common in greater than 1000 × 10 /L, and an increase in marrow megakaryocytes,
9
core-binding factor-associated leukemias, although only KIT mutations especially micromegakaryocytes. Most of the recurring translocations
1
confer a poor prognosis. 33 described above occur in younger patients with a median age in the 30s,
whereas other abnormalities, such as del(5q), or −7/del(7q), occur in
Translocation 15;17 patients with a median age greater than 50 years. Moreover, many of the
The t(15;17)(q24.1;q21.1) (see Fig. 13–3) is specific for acute promye- latter patients have occupational exposure to mutagenic agents, such as
locytic leukemia (APL) and has not been found in any other disease. solvents, petroleum, and pesticides.
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Rare variant translocations, which occur in less than 2 percent of cases,
include the t(11;17)(q23.2;q21.1) and t(5;17)(q35.1;q21.1), which result Mutations
in the ZBTB16 (PLZF)-RARA and NPM1-RARA fusion proteins, The prognosis of patients with AML is also determined by mutations,
respectively. Establishing the diagnosis of APL with the typical t(15;17) most commonly of the FLT3, NPM1, CEBPA, or KIT genes (Table
38
is important, because this disease is sensitive to therapy with all-trans 13–3). Mutations of the FLT3 gene, including both point mutations
retinoic acid, whereas other cases of AML and some of the APL-like within the tyrosine kinase domain and ITDs, are among the most com-
disorders associated with the variant translocations do not respond to mon genetic changes seen in AML, occurring in 15 to 35 percent of
this treatment (Chap. 88). The t(15;17) results in a fusion retinoic acid cases. FLT3-ITD mutations may occur in any subtype of AML, but are
receptor-α protein (PML-RARA). The oncogenic potential of the APL most common in APL and AML with a normal karyotype, and are asso-
fusion proteins appears to result from the aberrant repression of RARA- ciated with a poor prognosis, particularly in those cases with loss of the
39
mediated gene transcription through histone deacetylase (HDAC)- remaining wild type FLT3 allele. Mutations of the FLT3 tyrosine kinase
dependent chromatin remodeling. Genetic mutations that cooperate domain (codons 835 or 836 of the second tyrosine kinase domain) are
39
with PML-RARA include FLT3 internal tandem duplications (ITDs), noted in 5 to 8 percent of AML. Mutations of NPM1 also occur fre-
observed in 35 percent of patients. quently in AML (35 percent of adult cases, and 80 to 90 percent of acute
monocytic leukemia), but are less frequent in patients with recurring
cytogenetic abnormalities. In the absence of FLT3 mutations, NPM1
Translocations Involving 11q mutations are associated with a favorable prognosis. NPM1 mutations,
40
Recurring translocations involving 11q23.3 are seen in approximately most commonly involve exon 12, resulting in alterations at the C-termi-
35 percent of acute monocytic leukemia patients and are of great inter- nus, that is, replacement of tryptophan(s) at position 288 and 290, and
1,35
est in acute leukemia for at least three reasons. First, there are more aberrant localization of the protein to the cytoplasm. CEBPA mutations
than 50 different recurring rearrangements that involve 11q23.3 and, (6 to 15 percent of all AMLs), are often biallelic, and are usually asso-
thus, along with 14q32.3, 11q23.3 is one of the bands most frequently ciated with intermediate risk cytogenetics, but are generally associated
involved in rearrangements in human tumor cells. 35,36 The most com- with a favorable prognosis. Mutations of KIT are noted in 2 percent
38
mon breakpoints in the translocation partners include 1p32, 4q21.3, of AMLs, and have prognostic significance among AMLs with t(8;21)
and 19p13.3 in ALL (Chap. 91), and 1q21, 2q21, 6q27, 9p21.3, 10p12, and inv(16)/t(16;16) (20 to 25 percent), in which they are associated
17q25, 19p13.3, and 19p13.1 in AML (Chap. 88). Second, these translo-
cations occur in both lymphoid and myeloid leukemias. One common
translocation in infants, t(4;11)(q21.3;q23.3), has a lymphoblastic phe- TABLE 13–3. Gene Mutations in MDS and AML
notype, whereas other translocations, such as the t(9;11)(p21.3;q23.3) Disease
(see Fig. 13–3) and t(11;19)(q23.3;p13.1), are common in acute mono-
cytic leukemias. Finally, translocations involving 11q23.3 have a very Mutated Gene MDS AML t-MDS/t-AML
unusual age distribution, comprising about three-quarters of the chro- FLT3 (ITD) 2.4% 15–35% 0%
mosome abnormalities in leukemia cells of children younger than 1 year FLT3 (TKD) 1% 5–8% <1%
of age. With the exception of the t(9;11) which may have an inter-
35
mediate outcome, translocations of 11q23.3 are associated with a poor NRAS 10–15% 10% 10%
outcome. Translocations of 11q23.3 involve KMT2A/MLL, a very large KIT D816 ~1% 2% NA
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gene (>100 kb) with multiple transcripts of 12 to 15 kb. KMT2A pro- KMT2A (ITD) 3% 7% 2–3%
tein is a histone methyltransferase that assembles in protein complexes
that regulate gene transcription via chromatin remodeling. All of the RUNX1 10–15% 12% 15–30%
36
KMT2A translocations identified to date result in fusion proteins. TP53 5–10% 5–10% 25–30%
PTPN11 ~1% ~1% 3%
Trisomy 11 NPM1 Rare 35% 4–5%
Trisomy 11 is a rare abnormality, noted as a sole aberration in 1 to 2 per-
cent of MDS or AML, and confers an unfavorable outcome. It is nota- CEBPA 1–8% 6–18% Rare
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ble that an ITD of the KMT2A gene is detected in 90 percent of AMLs JAK2 V617F 2–5% 2–5% 2–5%
with +11 as the sole abnormality and in 10 percent of AML cases with DNMT3A 8% 10% 16%
a normal karyotype. The rearrangement is the result of a duplication of

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