Page 957 - Hematology_ Basic Principles and Practice ( PDFDrive )

840 Part VII Hematologic Malignancies

frequently observed in older children. These 1p32 rearrangements are
less frequent in adult ALL. TAL1-positive ALL is characterized by an
+
+
arrest in differentiation at the CD4 CD8 stage of thymocyte devel-
1 2 3 4 5 opment, when TAL1 gene is normally silent. TAL1 gene encodes a
transcription factor and several of the core components of the tran-
scription complex include GATA3, LIM domain only, and RUNX1.
TAL2, residing at 9q32, is detected in rare t(7;9)(q34;q32) rear-
rangement as a result of juxtaposition of TAL2 to TCRB. LYL1,
6 7 8 9 10 11 12 originally described as a fusion partner of TCRB in rare (7;19)
(q34;p13), and is associated with poor prognosis. Rearrangements of
HOX11L2, which include cryptic t(5;14)(q35;q32), t(5;7)(q35;q21),
and other variants, occur at a frequency of 24% in children and
13 14 15 16 17 18 represent a predictor of poor outcome, regardless of treatment strate-
gies. Similarly, the presence of t(10;11)(p13;q14), which results in
the CALM-MLL10 fusion gene and occurs at a frequency of 2% to
5% in children, may be associated with poor outcome. Abnormalities
19 20 21 22 X Y of HOX11 are more common in adults than in children (31% versus
7%) and are associated with t(10;14)(q34;q24) and t(7;10)(q34;q24).
Fig. 56.59 A COMPLEX KARYOTYPE FROM A PATIENT WITH t(10;14) is the most frequent chromosomal translocation in patients
HAIRY CELL LEUKEMIA. In this karyotype there are nine complex with T-cell ALL. It is associated with excellent outcome in both
structural abnormalities as indicated by arrows and the karyotype is 47, XY, children and adults with t(10;14) and in these patients the homeobox
del(5)(q15;q31), der(8)t(3;8)(p21p26;q24), der(17)t(1;17) (p36.1;p13) gene HOX11 is fused with TCRD. The coding regions of HOX11 are
t(17;21)(q25q22.2), −21, +r(21)×2. not disturbed by the translocation. In the variant translocation
t(7;10)(q35;q24), HOX11 is juxtaposed to TCRB, which results in
overexpression of normal HOX11 mRNA by bringing HOX11 under
sequence analysis revealed a mean BRAF-V600E-mutant allele fre- the influence of TCR promoter sequences.
quency of 4.9% in human hematopoietic stem cells from patients MLL rearrangements are present in 8% of T-cell ALL cases
with HCL and functional studies showed that these cells have self- (see Fig. 56.33). The most frequent MLL translocation partners in
renewal capacity, indicating that this mature B-cell malignancy origi- T-cell ALL include ENL, which results from t(11;19)(q23;p13.3)
nates within the hematopoietic stem cell compartment. Detection of and is associated with a better prognosis than T-cell ALL with
the BRAF-V600E mutation by PCR is the gold standard for the other fusion partners. GEP has characterized T-cell ALL with
genetic diagnosis of HCL. MLL rearrangements as a distinct molecular subtype. Homeobox
genes, regulators of embryonic development, are known targets of
MLL and are overexpressed in patients with T-cell ALL and MLL
T-CELL LYMPHOPROLIFERATIVE NEOPLASMS rearrangements.
Dysregulation of NOTCH, tyrosine kinase genes (ABL1, JAK2),
This is a diverse group of hematologic disorders that includes T-cell and LIM domain genes (LMO1, LMO2) is also common in T-cell
ALL and T-cell CLL/PML, as well as several indolent T-cell disorders, ALL. NOTCH1 is a fusion partner of TCRB in t(7;9)(q34;q34.3).
large granular lymphocyte leukemia, natural killer leukemia/ These mutations are present in 56% of T-cell ALL cases. The
lymphoma, and anaplastic large cell lymphoma (ALCL). NOTCH1 gene is important in lymphoid lineage specification, and
T-cell ALL represents 15% of childhood ALL cases and 25% of resequencing of functional domains of NOTCH1 have revealed that
adult ALL cases. At diagnosis, approximately 50% of patients have a activating NOTCH1 mutations are present in most primary pediatric
normal karyotype. Table 56.11 lists recurrent cytogenetic and and adolescent molecular cases of T-ALL as well as in adult ALL.
molecular genomic changes associated with T-cell ALL and Table Mutations in the heterodimer domain as well as ITD result in con-
56.18 lists the frequency of recurrent chromosomal abnormalities in stitutive ligand-independent activation of NOTCH1.
T-ALL. Immunophenotypic and gene expression analyses are consis- The LIM family of genes is found at the breakpoint of rare but
tent with genetic heterogeneity in T-cell ALL, reflecting, to some consistent chromosomal translocations in T-cell ALL. LMO1, located
degree, distinct stages of T-cell maturation arrest. at 11p15, is involved in t(11;14)(p15;q11). LMO2, located at 11p13,
One of the common themes in T-lymphoid malignancies is the is involved in t(11;14)(p13;q11) and t(7;11)(q35;p13). As an onco-
juxtaposition of the TCR gene enhancer element adjacent to a variety genic transcription regulator, LMO2 overexpression in erythroid and
of transcription factors located at or near breakpoints on the partner T cells leads to a differentiation arrest, which is a prerequisite for
chromosome. The chromosomal bands most frequently involved are development of T-cell malignancies.
14q11, where TCRA and TCRD are located (see Fig. 56.60); 7q35, The MYB gene, which is localized on chromosome 6, band q23.3,
the site of TCRB; and 7p15, the site of the TCRG. TCR translocations is rearranged in a rare T-cell ALL subtype observed in young patients
are found in approximately 35% of T-cell ALL cases (Table 56.17). (median 2.2 years). Two types of recurrent MYB genomic alterations
The rearrangements of TCRB and TCRG are relatively rare, whereas are found in T-cell ALL: (a) a reciprocal t(6;7)(q23;q34) that results
14q11 rearrangements involving both TCRA and TCRD are frequent in juxtaposition of MYB near TCRB regulatory sequences on chromo-
in T-lymphoid neoplasms (see Table 56.13). some 7 and (b) a short genomic tandem duplication, identified using
In children, the overall frequency of T-cell ALL translocations is genome-wide copy-number analysis. Both rearrangements are cyto-
40% to 50%, and several molecular/cytogenetic abnormalities have genetically cryptic. The breakpoints in t(6;7) are subtelomeric and
prognostic relevance (see Table 56.14). TAL1 rearrangements include usually missed. The translocation was discovered using a locus-specific
30
t(1;14)(p32;q11), t(1;7)(p32;q35), rare t(1;3)(p32;p21), t(1;5) FISH probe for MYC. The tandem MYB duplication is cryptic
(p32;q31) and t(14;19)(q11.2;q13.1) (Fig. 56.61). In general, TAL1 using both conventional cytogenetics and locus-specific FISH. It is
rearrangements are submicroscopic and best identified with FISH. mapped using high-density oligonucleotide aCGH. Discovery of
Disruption of TAL1 is frequently associated with a submicroscopic MYB highlights the strength of high-density aCGH in identifying
interstitial deletion (90 kb) between the 5′ untranslated region of the cryptic copy-number abnormalities associated with leukemia.
TAL1 (1p32) and the SIL (STIL) genes (1p32) in 9% to 26% of cases Although only 1% of Ph-positive ALL have a T-cell phenotype,
depending on the different studies. The SIL-TAL1 fusion product the ABL1 gene, is also involved in fusion with NUP214 (9q34.11),
gives rise to inappropriate expression of TAL1 protein. Among 382 creating the NUP214-ABL1 chimeric gene/t(9;22)(q34.11–q22.1),
children, 16% showed the presence of SIL-TAL1, which was more which is identified in up to 6% of T-cell ALL. This fusion gene is