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1008 Part VII Hematologic Malignancies

of structurally intact genes. By contrast, the chromosomal transloca- childhood T-cell ALL cases. 75–80 However, TAL1 is aberrantly
tions that often occur in precursor B-cell ALL generally lead to the expressed in the leukemic cells of 60% of children and 45% of adults
expression of chimeric fusion proteins. with T-cell ALL, implicating additional pathogenic mechanisms
leading to TAL1 overexpression. One such recently described mecha-
Activation of Structurally Intact Transcription Factors nism is an activating mutation of a noncoding gene-regulatory
element, which is described later in this chapter. TAL1 acts as a
MYC in Mature B-Cell Acute master regulatory protein during early hematopoietic development
81,82
and is required for the generation of all blood cell lineages.
Lymphoblastic Leukemia However, it does not seem to be required for the generation and
function of hematopoietic stem cells (HSCs) during adult hemato-
83
The vast majority of cases of mature B-cell ALL (Burkitt leukemia) poiesis. TAL1 is a bona fide T-cell ALL oncogene, as its aberrant
are characterized by a translocation that places one allele of MYC expression in murine T-cell progenitors induces T-cell ALL. 84,85
from chromosome 8 under the control of the regulatory elements of TAL1 binds DNA in complex with other transcription factors
an Ig gene, either the heavy-chain gene on chromosome 14q32 or the including TCF3 (also known as E2A), HEB, LMO1/2, GATA3,
κ or λ light-chain genes on chromosomes 2 and 22, respectively. RUNX1 and MYB. 86–88 TAL1 binding can activate or repress expres-
These translocations are oncogenic because they result in lineage- sion of its target genes, and a number of these targets have been
specific overexpression of MYC, a prototypical basic helix-loop-helix implicated in T-cell transformation. 89,90 In murine T-cell progenitors,
91
oncogenic transcription factor. 48–56 The mechanisms through which TAL1 expression inhibits TCF3 transcriptional activity, and loss of
the MYC oncoprotein exerts its potent oncogenic effects have been TCF3 function induces T-cell leukemias in mice, 92,93 supporting a
the subject of intense investigation. MYC has been estimated to regu- role for TAL1-mediated inhibition of TCF3 function in leukemogen-
57
late the expression of 15% of the genome, and leads to the tran- esis. The TAL1 complex binds and upregulates expression of several
scriptional activation of a large number of genes involved in cell of its own core components, including TAL1, GATA3, RUNX1, and
58
division, growth, metabolism, adhesion, and motility. MYC also MYB, thus forming a positive-feedback loop that reinforces activity
exerts posttranscriptional effects on gene expression by regulating of this oncogenic transcriptional complex. 88,90 TAL1 also upregulates
microRNA expression and ribosome biogenesis. 59–62 MYC exerts its expression of TRIB2, a gene whose overexpression in mouse bone
94
transcriptional activity via the formation of heterodimers with its marrow cells induces myeloid leukemia, and whose expression is
90
DNA-binding partner protein MAX. MYC-MAX heterodimers bind required for the survival of TAL1-overexpressing T-cell ALL. Fur-
to canonical hexameric E-box DNA sequences (5′-CACGTG-3′), thermore, TAL1 also upregulates expression of the microRNA
63
where they activate transcription. MAX can also heterodimerize mir223, which promotes leukemic cell survival by downregulating
64
with other basic helix-loop-helix proteins, including MAD, MXI-1 expression of the FBXW7 tumor suppressor. 95
65
66
(MAD2), and MNT. Whereas transcriptional activation by The LIM-only domain genes, LMO1 and LMO2, are also
MYC-MAX complexes promotes proliferation, binding by involved in recurrent chromosomal translocations in T-cell ALL. 96–98
MAD-MAX and other MAX heterodimers produce opposite effects. These genes encode transcription factors that interact with TAL1 in
For example, MAD inhibits MYC function both by competing with erythroid cells and in T-cell leukemias. 99–101 Homozygous disrup-
MYC for binding to MAX and by directly inhibiting transcription. tion of LMO2 in mice phenocopies the hematopoietic defect of
Recent work has revealed that a major consequence of MYC TAL1 knock-outs, suggesting that these proteins function together
overexpression is the global amplification of gene expression. Inves- during hematopoietic development. 102,103,104,105 In addition, overex-
tigation of transcriptional regulation mechanisms has revealed two pression of LMO1 or LMO2 in murine thymocytes leads to T-cell
distinct steps in the regulation of gene expression by transcription transformation 106–110 and accelerates the onset of leukemias in TAL1
factors. First, RNA polymerase II and its associated transcriptional transgenic mice. 101
apparatus are loaded onto a gene promoter by one set of transcription
factors, 67,68 but RNA polymerase is often initially “paused” near the
proximal promoter. 69–71 Subsequent release from transcriptional pause Homeobox Genes
is a distinct and highly regulated step in the control of gene expres-
sion. Unexpectedly, recent studies have revealed that a major conse- The homeobox gene TLX1 (also known as HOX11) is the found-
quence of MYC overexpression is the release of transcriptional pause ing member of a family of homeobox genes that includes TLX2
at genes that were already loaded with RNA polymerase, rather than (HOX11L1) and TLX3 (HOX11L2), each of which plays key roles
the recruitment of RNA polymerase to new target genes. 72–74 These in embryonic development. 111–114 TLX1 was originally isolated from
findings support a model in which MYC overexpression functions to the recurrent t(10;14) translocation in T-cell ALL, 27,115–117 and is aber-
amplify the expression of genes that are already being transcribed, rantly expressed in 5% of pediatric and approximately 25% of adult
thus “locking in” a cell’s existing transcriptional program. The acqui- T-cell ALL cases. 118–120 TLX3 is also involved in a recurrent t(5;14)
121
sition of a MYC-activating lesion in a cell with a highly proliferative (q35;q32) translocation, and is overexpressed in approximately
gene expression program that is normally transient, such as an 25% of pediatric but only 5% of adult T-cell ALL. 118,120,122–124 TLX1
immature B-cell progenitor, can lock this cell in this highly prolifera- and TLX3 encode very similar proteins, suggesting they have similar
tive state, thus providing one mechanism to explain MYC-driven oncogenic mechanisms. Overexpression of TLX1 or TLX3 induces
oncogenesis. differentiation arrest at a cortical stage of T-cell development, an
effect that is mediated by TLX-induced transcriptional repression of
TAL1 and LMO Genes in T-Cell Acute the pre–T-cell receptor alpha, whose expression is required for pro-
125,126
gression beyond this stage in normal T-cell development.
TLX1
Lymphoblastic Leukemia expression in murine T-cell progenitors induces T-cell ALL, and these
tumor cells have a defective mitotic checkpoint due to transcriptional
127
In leukemia with a T-cell phenotype, the breakpoints of recurrent repression of the checkpoint kinase CHEK1. These findings, together
chromosomal translocations consistently juxtapose TCR gene regula- with the previous observation that TLX1 binds the catalytic subunits
tory elements, which are highly active in committed T-cell progeni- of the phosphatases, PP2A and PP1, and disrupts the G2/M check-
128
tors, to the protein-coding sequence of oncogenic transcription point, thus provide a mechanistic explanation for the association
factors, which then become aberrantly overexpressed as a result of of TLX1/TLX3 overexpression with aneuploidy, which is otherwise
127
these translocations. The best characterized of the oncogenic tran- rare in human T-cell ALL. RUNX1, which is directly bound and
scription factors involved is TAL1 (; also known as SCL). TAL1 repressed by TLX1 and TLX3, has been implicated as a downstream
is overexpressed as a result of the recurrent t(1;14) translocation mediator of the oncogenic function of these transcription factors in
or intrachromosomal deletions in approximately one-fourth of T-cell ALL. 129