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Chapter 64 Pathobiology of Acute Lymphoblastic Leukemia 1017

addition to their well-established functions as transcriptional activa-
tors, LEF/TCF transcription factors can also act as transcriptional Ribosomal Protein Gene Mutations in T-Cell Acute
repressors when bound to Groucho/TLE family members in the Lymphoblastic Leukemia
443
absence of β-catenin activation. Although the precise mechanisms
responsible for the pathogenic effect of LEF1 inactivation in T-cell Mutations in ribosomal proteins that lead to impaired ribosome
ALL have not yet been established, one potential explanation is biogenesis and function are well characterized in disorders of normal
that LEF1 may actively repress MYC in T-cell ALL cells lacking hematopoiesis, such as Diamond-Blackfan anemia and in 5q- myelo-
β-catenin activation, and that LEF1 inactivation in this context dysplastic syndrome; however, until recently they were not known
may promote maximal MYC overexpression downstream of other to be associated with the development of ALL. Using whole-exome
oncogenic lesions that drive MYC overexpression, such as NOTCH1 sequencing, recurrent mutations in RPL5 and RPL10 have been iden-
457
mutations. tified in pediatric T-cell ALL. Moreover, gene expression analysis of
pediatric T-cell ALL samples has identified monoalleleic focal dele-
BCL11B Inactivation in T-Cell Acute tions of RPL22, a ribosomal gene that is required for the development
458
of normal T-cell progenitors. While functional studies investigating
Lymphoblastic Leukemia ribosomal proteins in T-cell ALL have revealed a role transformation
and cell proliferation, the exact mechanism through which this may
The BCL11B transcription factor is required for normal T-cell provide an advantage to the lymphoblasts remains unknown. 457,458
development. In murine T-cell progenitors, inactivation of BCL11B
leads to developmental arrest at double-negative stages, acquisition
of natural killer-like features, and aberrant self-renewal activity. 444–447 Abnormalities of Leukemia Cell Ploidy
Monoallelic BCL11B deletions or point mutations have recently been
identified in 9%–16% of primary T-cell ALL patient samples. 127,448 Abnormalities of chromosome number, which generally occur in the
The point mutations identified typically occur within the DNA- absence of specific chromosomal translocations, have important
binding domains of BCL11B and are predicted to disrupt their ability prognostic and biologic implications in childhood ALL.
to bind DNA. Moreover, previous work in murine models has shown
that BCL11B suppresses T-lymphoblastic malignancies induced by
p53 haploinsufficiency, radiation, or the BCR-ABL1 oncogene, 449,450 Hyperdiploidy
and BCL11B inactivation is a particularly common cooperating
lesion in murine T-cell ALL induced by the TLX1 oncogene or by Found in 25%–30% of childhood ALL cases, high hyperdiploidy,
ATM deficiency. 127,451 In human T-cell ALL, recurrent cryptic t(5;14) defined as the presence of 51–65 chromosomes in the leukemic clone,
183
(q35;q32) translocations juxtaposing BCL11B and TLX3 have been is a powerful favorable prognostic indicator in childhood ALL.
described, which result in BCL11B gene regulatory elements driving Trisomies of chromosomes 4, 10, and 17 impart a particularly good
overexpression of TLX3. 121,452,453 These translocations were long prognosis, while high hyperdiploidy in the absence of these trisomies
459
thought to be pathogenic because of the resultant overexpression of is less of a favorable prognostic factor. Near triploid (68–80 chro-
the TLX3 oncogene. However, these recent findings indicate that mosomes) and near tetraploid ALL (>80 chromosomes) appear to be
both BCL11B inactivation and TLX oncogene overexpression are biologically distinct entities with less prognostic significance. Patients
important pathogenic consequences of this translocation, thus repre- with high hyperdiploidy can expect favorable long-term outcomes,
senting two oncogenic events from a single genomic lesion. BCL11B and typically present with favorable prognostic indicators, such as age
has recently been implicated as a core component of the SWI/SNF between 2 and 10 years, a low white blood cell count, and precursor
chromatin remodeling complex, a key tumor suppressor in diverse B-cell immunophenotype. 460–462 The mechanisms accounting for the
human malignancies. Thus, SWI/SNF complex inactivation provides favorable outcome of patients with hyperdiploid ALL remain elusive
463
one potential mechanism to explain the pathogenic consequences of but may reflect an increased sensitivity to antimetabolite therapy
BCL11B in T-cell ALL. 454 and a greater propensity to undergo apoptosis. 152
PHF6 Mutations in T-Cell Acute Hypodiploidy
Lymphoblastic Leukemia
In marked contrast to the favorable outcomes associated with hyper-
T-cell ALL has a conspicuous male predominance, suggesting the diploidy, the occurrence of hypodiploidy (<45 chromosomes) carries
potential involvement of tumor suppressors on the X-chromosome. an extremely poor prognosis. 183,464 A recent large-scale genomic study
Targeted mutational analysis of the X chromosome revealed one such has revealed that hypodiploid ALL comprises two molecularly distinct
465
candidate tumor suppressor, PHF6, which is a nucleolus ribosomal biologic entities. Near-haploid ALL (24–31 chromosomes) com-
RNA (rRNA) promoter-associated protein that directly interacts with monly harbors activating mutations in the RAS pathway, with activat-
upstream binding factor through its PHD1 domain and suppresses ing mutations of RAS genes or loss-of-function mutations of its
rRNA. Germline mutations of PHF6 were first described in associa- negative regulator NF1 being particularly common. By contrast, low
tion with Borjeson-Forssman-Lehmann syndrome (OMIM 301900), hypodiploid ALL (32–39 chromosomes) has an exceptionally high
which is associated with severe mental retardation and facial dysmor- frequency of p53 mutations, which are otherwise very rare in ALL.
phisms but until recently had not been associated with T-cell ALL. Strikingly, nearly half of these cases had p53 mutations identified in
Ferrando and colleagues identified somatic nonsense and frameshift remission DNA, strongly suggesting these patients have germline p53
mutations leading to loss of PHF6 expression in 16% of pediatric mutations. Despite the differences in underlying genetic alterations,
and in 38% of adult T-cell ALL patient samples, and which were both near haploid and low hypodiploid ALL are associated with
associated with overexpression of the TLX1 or TLX3 oncogenic activation of RAS and PI3K signaling pathways, and preclinical data
455
transcription factors. The pathogenic consequences of PHF6 support the potential therapeutic utility of PI3K pathway inhibitors
inactivation in T-cell ALL are not fully understand and remain an for these patients. 465
area of ongoing investigation. However, recent work has suggested
that PHF6 plays a role in cell proliferation, and that loss of PHF6
leads to arrest at the G 2/M checkpoint and increased DNA damage Polysomy 21
at the ribosomal locus. Thus, it is postulated that PHF6 acts as a
tumor suppressor with a regulatory role in rRNA synthesis and Gains of additional copies of chromosome 21 are the most common
genome maintenance. 456 somatic aneuploidy in precursor B-cell ALL, and patients with