Page 937 - Hematology_ Basic Principles and Practice ( PDFDrive )

820 Part VII Hematologic Malignancies

BCR-ABL1-like ALL is a newly described ALL subtype lacking BCR- patients with t(4;11) have secondary abnormalities; the most frequent
ABL1, but with a similar expression profile to BCR-ABL1+ leukemia. are +X, i(7q), abnormalities of 9p, including i(9q), and +8. The
This new “BCR-ABL1-like” (“Ph-chromosome-like”) ALL includes outcomes of patients with t(11;19) is generally poor, especially in
approximately 15% of all precursor B-cell ALL in children and 17% children younger than 1 year of age. The most frequent additional
of adults with ALL and is associated with higher relapse rate and abnormalities in patients with t(11;19) are +X, +8, and del(6q).
lower EFS (see Fig. 56.41). According to the currently used risk Other less common MLL translocations include t(9;11)
stratification system, 43% of the “BCR-ABL-like” patients are clas- (p22;q23)/MLL-MLLT3, t(10;11)(p13–15;q23)/MLL-MLLT10 and
sified as having high-risk disease. Large-scale genomic profiling and others. A large multiinstitutional study has determined that second-
sequencing studies of over 1700 childhood and young adult patients ary aberrations do not affect prognosis of children with ALL and
with ALL has revealed rearrangements of ABL-class genes, rearrange- t(4;11),t(11;19) or other MLL translocations.
ments of JAK2, EPOR, and CRLF2. ABL-class rearrangements result Secondary forms of ALLs are rarely reported but the majority of
in the expression of fusion genes that activate ABL1, ABL2, CSFR1, them are associated with MLL rearrangements, the most frequent
and PDGFRB. In this group of patients IKZF-1 deletions occur in being t(4;11). Most of these patients have received topoisomerase II
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40% of pediatric and in 46% of adult patients. CRLF2 (Xp22.33/ inhibitors which are known to cause double-strand DNA breaks.
p11.3) rearrangements are observed in approximately 50% of patients t(8;14)(q24;q32) is seen in fewer than 5% of all patients with
with BCR-ABL1-like ALL. The gene encodes for cytokine receptor- ALL (children and adults) (Fig. 56.45). Variant translocations t(8;22)
like factor 2, also known as thymic-stromal–derived lymphopoietin (q24;q11) and t(2;8)(p12;q24) are seen in less than 1% of children
receptor which in combination with the interleukin-7 receptor and adults. These cells express CD10, CD19, CD20, and surface
forms the receptor for the thymic stromal lymphopoietin. CRLF2- IgM immunophenotype. This form of ALL has extremely poor
rearranged leukemic cells have activated JAK-STAT and PI3K signal- prognosis. The same translocation is found in Burkitt lymphoma
ing pathways. (BL), and both entities likely represent the same disease with different
t(1;19)(q23;p13.3)/TCF3/PBX1 occurs in 5% to 6% of patients manifestations. The majority of adult patients with t(8;14) die within
with B-cell precursor childhood and adult ALL. However, among 1 year of diagnosis. Approximately 4% of children and 11% of adult
patients with a pre-B (cytoplasmic Ig–positive) t(1;19) is found in pre–B-cell precursor ALL have recurrent IGH translocations usually
approximately 25% of cases (see Fig. 56.32E). Cytogenetically, two identified by cytogenetics or FISH. The CRLF2 gene, which maps to
forms of t(1;19) have been identified: 25% of cases have a balanced the pseudoautosomal region 1 of the sex chromosomes, is the gene
reciprocal t(1;19), whereas 75% have a rearrangement of unbalanced that is most frequently targeted in 20% to 26% of IGH translocations
der(19)t(1;19)(q23;p13.3). The unbalanced der(19)t(1;19) arises in pre–B-cell precursor ALL. IGH-CRLF2 rearrangements result from
from the initial trisomy of chromosome 1 followed by the t(1;19) the cryptic t(Y;14)(p11;q32) or t(X;14)(p22;q32). The second most
translocation, with subsequent loss of the derivative chromosome 1. frequent IGH translocation resulting in t(14;19)(q32;q13), resulting
More than 95% of t(1;19) are associated with the TCF3–PBX1 in IGH-CEBP chimeric fusion. The third most frequent translocation
chimeric gene protein product which arrests cell differentiation. The partner involves CEBPD gene (8q11) resulting in t(8;14)(q11;q32)
TCF3 gene (originally identified by the binding of E2A proteins to and IGH-CEBPD fusion, which is primarily found in children and
the kE2DNA sequence motif contained in the Ig κ light-chain young adults and is strongly associated with Down syndrome (about
enhancer) on chromosome 19, band p13.3, is fused to the PBX1 30% of cases). This subgroup frequently have a gain of X chromosome,
(homeobox) gene on chromosome 1, band q23. Approximately 1% trisomy 21 as an acquired abnormality, and the Ph chromosome/t(9;22)
of pediatric patients with B-ALL have a variant t(17;19)(q21– (;q34;q11). The t(14;19)(q32;q13)/IGH-EPOR appears to be causally
q22;p13) translocation resulting in two different genomic rearrange- related to pre–B-cell precursor ALL because it always appears always
ments. The first is the fusion between the HLF gene (breakpoint in as the single abnormality. The inv(14) (q11q32)/ins(14;14)(q11;q32)
intron 3) on chromosome 17 and the TCF3 gene (within intron 13) leads to IGH-TRA/D, which represent a rearrangement mediated by
on chromosome 19, associated with disseminated intravascular an interlocus site-specific recombination event between IGH and the
coagulopathy. The second is the breakpoint in intron 12 of TCF3 TRA and TRB genes. The t(14;20)(q32;q13) results in IGH-CEBPB.
and intron 3 of HLF, which is associated with hypercalcemia. In Collectively, patients with IGH translocations may be included in a
contrast to ETV6-RUNX1 rearrangements, which have a prenatal subgroup of pre–B-cell precursor ALL.
origin, current evidence suggests a postnatal etiology for t(1;19) Abnormalities of the short arms of chromosome 9 (p21–22) occur
translocations. at a frequency of 7% to 13%. In adults the presence of del(9p)
Currently, it is thought that an unbalanced der(19) in pediatric appears to be associated with a favorable outcome, whereas in children
patients with ALL is associated with significantly improved outcome with ALL, del(9p) is associated with poor outcome. The most fre-
as compared with patients with balanced t(1;19. In adults as the sole quent abnormalities are co-deletions of two genes, CDKN2A and
abnormality, t(1;19)/der(19)t(1;1.9) is associated with an intermedi- CDKN2B, as well as the interferon α and β genes found in many
ate prognosis; however, within the context of a hyperdiploid karyo- cases. Among the structural rearrangements involving the short arms
type, it is associated with a poor prognosis. Patients with TCF3-PBX1 of chromosome 9, t/dic(9;12)(p11–12;p11–13) is a rare recurrent
fusion also display PAX5 (19p13.2) haploinsufficiency, detectable abnormality associated with L1 morphology (FAB classification), a
both by conventional and molecular cytogenetics. A variant t(17;19) pre–B-cell phenotype, and an excellent prognosis.
rearrangement is associated with a poor prognosis. A recent study of The IKZF1 gene at 7p12.2 codes for IKAROS, an essential
adult patients with ALL has suggested that prognosis of patients with transcription factor in hematopoiesis primarily involved in lymphoid
t(1;19) can be substantially improved by the treatment with hyper- differentiation and is an essential player in the regulation of both
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CVAD regimen. Both t(1;19) and t(17;19) are easily identifiable by T- and B-cell lineage specification. The gene is composed of eight
conventional cytogenetics, FISH, and RT-PCR, the latter two meth- exons, spanning a total of 6.2 kb and coding for a 519-amino acid
odologies are particularly useful in posttreatment specimens that are protein. Deletions of IKZF1 have been reported in 15% of pediatric
cytogenetically normal. and 30% to 50% of adult patients with ALL, and in 75% of
In ALL, the most frequent MLL (KMT2A) translocations include Ph-positive B-cell ALL. Both focal and nonfocal IKZF1 deletions
t(4;11) (1%–2% incidence in children and two-thirds of MLL- have been shown to be associated with an increased risk of relapse
positive adults) (see Fig. 56.33) leading to a MLL-AFF1 (AF4) fusion and decreased EFS in both pediatric and adult ALL. Most laboratories
and t(11;19)(q23;p13.3) (see Fig. 56.32L) resulting in MLL-MLLT1 use SNP array technique to detect IKZF1 deletion. Recent genomic
(ENL) fusion. These abnormalities are present in more than 80% of studies of patients with ALL have confirmed a higher hazard of
patients with infant leukemia and 10% of childhood and adult MLL- relapse in adult ALL with focal IKZF1 deletions.
positive leukemia. MLL rearrangements are associated with a poor Other chromosomal abnormalities detected in nonrandom fashion
outcome in both children and adults (see Acute Myeloid Leukemia, in adult patients with ALL include deletions, both terminal and
earlier, and T-Cell Lymphoproliferative Diseases, later). One-third of interstitial, of the long arm of chromosome 6, and isochromosomes