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Chapter 64 Pathobiology of Acute Lymphoblastic Leukemia 1009

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The cluster of HOXA genes on chromosome 7 is affected by a or p53. In TCF3-HLF–expressing human ALL cells, inhibition of
recurrent chromosomal inversion that places it in the vicinity of TCF3-HLF function by expression of a dominant-negative form of
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TCR beta gene regulatory elements, leading to aberrant expression TCF3-HLF results in apoptosis induction. HLF is the mammalian
of the entire HOXA cluster in approximately 5% of cases of T-cell homologue of the worm protein ces-2, a transcription factor that is
ALL. 130,131 Many of these cases also carry cooperating oncogenic necessary for the death of two specific nerve cells during Caenorhab-
lesions consisting of NOTCH1 gene mutations and deletions of ditis elegans development. 154–156 This pathway, which is evolutionarily
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9p21. This new translocation that directly activates HOXA gene conserved, is inhibited by the TCF3-HLF fusion. Thus, in contrast
expression provides additional evidence for the role of aberrant to the proapoptotic role of the wild-type HLF homolog (ces-2) in
HOXA activation in leukemogenesis and in the pathogenesis of worms, TCF3-HLF blocks apoptosis by inducing the expression of
MLL- and CALM-AF10–rearranged leukemias, as reviewed in more SLUG, a transcription factor that blocks DNA damage-induced
detail later. apoptosis in hematopoietic cells. 157–160 The t(17;19) is seen in less
than 1% of ALL cases, but is associated with characteristic clinical
features including adolescent age, disseminated intravascular coagula-
Chimeric Transcription Factor Oncogenes tion and hypercalcemia at diagnosis.

Chromosomal translocations resulting in the formation of chimeric
proteins represents a second mechanism for aberrant transcription CALM-AF10 Fusion Gene in T-Cell Acute
factor activation, which is more prevalent in precursor B-cell ALL. Lymphoblastic Leukemia
These translocations juxtapose exons that encode the DNA-binding
and protein-binding domains of different genes, resulting in expres- The t(10;11)(p13;q14) is detected in approximately 3%–10% of
sion of a chimeric fusion protein. The generation of such fusions is T-cell ALL cases and in occasional AML cases. This translocation
facilitated by the modular structure of transcription factor genes, in results in the fusion of CALM (also known as PICALM), encoding a
which discrete exons encode particular functional domains. This protein with high homology to the murine clathrin assembly protein
feature of gene structure facilitates organismal evolution, but is com- ap3, with AF10, a gene identified as an MLL partner in the MLL-
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monly co-opted during oncogenesis. AF10 fusion resulting from the t(10;11)(p13;q23). Expression of
the CALM-AF10 fusion transcript has been associated with early
TCF3-PBX1 Fusion Genes in Precursor B-Cell arrest in T-cell development and to differentiation into the gamma-
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delta lineage in T-cell ALL. Additionally, aberrant upregulation
Acute Lymphoblastic Leukemia of HOX gene expression appears to be involved in CALM-AF10–
mediated leukemogenesis, at least in AML cells that carry this
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A well-known example of an oncogenic chimeric transcription factor translocation. Interestingly, analysis of a mouse model of CALM-
is the TCF3-PBX1 (also known as E2A-PBX1) rearrangement, which AF10–induced AML suggests that the leukemic stem cell in this
results from the t(1;19)(q23;p13) chromosomal translocation present model has lymphoid characteristics, and cells from human patients
in about 5% of all B-lineage ALLs and in 25% of cases with a pre-B with AML can be identified that have similar characteristics to
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(cytoplasmic Ig-positive) phenotype. 133,134 This translocation fuses the the disease-propagating cell in this animal model. More recent
two N-terminal transactivation domains of the TCF3 transcription evidence has demonstrated a dependence of CALM-AF10–mediated
factor on chromosome 19 to the DNA-binding domain of the leukemogenesis on the H3K79 methyltransferase DOT1L, thus
homeobox gene PBX1, leading to the expression of hybrid TCF3- implicating targeted therapy with DOT1L inhibitors in this ALL
PBX1 oncoproteins. 135–140 The transforming potential of TCF3-PBX1 subtype. 165,166
was first demonstrated by the rapid induction of AML in lethally
irradiated mice repopulated with hematopoietic progenitors trans-
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duced with TCF3-PBX1 genes. This fusion has also been shown to ETV6-RUNX1 (TEL-AML1) Fusions in Precursor
transform NIH-3T3 fibroblasts and induce T-cell lymphomas in B-Cell Acute Lymphoblastic Leukemia
transgenic mice. 142,143 Additional studies have shown that deletion of
one of the TCF3 activation domains diminishes its transforming Although most t(12;21) translocations are not detectable by standard
activity, but deletion of the PBX1 homeodomain has no effect. 143,144 cytogenetic analysis, this translocation is detectable by molecular
The presence of the TCF3-PBX1 translocation was originally associ- techniques in approximately 25% of childhood B-lineage ALL, which
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ated with a poor prognosis. However, this translocation no longer makes this the most common translocation in pediatric ALL (see Fig.
imparts an adverse prognosis in the setting of modern risk-adjusted 64.1). The ETV6-RUNX1 translocation often arises prenatally and is
protocols for childhood ALL. 134,146–148 likely to be the initiating mutation in at least a subset of ALL, as
evidenced by the identification of identical ETV6-RUNX1 transloca-
TCF3-HLF Fusion Genes in Early Pre-B Acute tions in identical twins with concordant ALL, and in retrospectively
analyzed neonatal blood specimens of children who were diagnosed
Lymphoblastic Leukemia with ALL many years later. 167,168 However, ETV6-RUNX1 alone is
not sufficient for leukemogenesis because the incidence of detectable
The t(17;19) is a rare recurrent chromosomal translocation that ETV6-RUNX1 fusions in the blood of normal newborns is about
fuses the N-terminal transactivation domains of TCF3 to the 100-fold greater than the incidence of leukemia. 169
C-terminal DNA-binding and dimerization domains of HLF, 149,150 The molecular mechanisms mediating ETV6-RUNX1–induced
a basic leucine zipper domain transcription factor. Although leukemogenesis remain poorly understood. This fusion gene encodes
the TCF3-HLF fusion protein can bind DNA either as a homodimer a chimeric protein that contains the helix–loop–helix (HLH) domain
or as a heterodimer with HLF and related proteins, no other PAR of ETV6 fused to nearly all of RUNX1 (also known as AML1 or
proteins are expressed in hematopoietic cells, and the TCF3-HLF CBFA2), including both the transactivation domain and the DNA-
fusion binds DNA as a homodimer in cells harboring the t(17;19). and protein-binding Runt homology domains. Both of these genes
Similar to TCF3-PBX1, TCF3-HLF can transform NIH-3T3 fibro- are found in other leukemia-related translocations, and both are
blasts, a process that requires the HLF leucine zipper domain and essential for normal hematopoiesis. ETV6 was first identified in the
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the TCF3 transactivation domains. TCF3-HLF can also induce t(5;12) in chronic myelomonocytic leukemia, where it is fused to the
lymphoid tumors in transgenic mice. 152,153 A major consequence platelet-derived growth factor receptor gene (PDGFRB), and is also
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of TCF3-HLF expression in lymphoid precursors is inhibition of fused to ABL, MN1, and EVI1 in AML and to JAK2 in T-cell ALL.
apoptotic cell death. In normal pro-B lymphocytes, expression of ETV6 is required for fetal hematopoiesis in the mouse. Interestingly,
TCF3-HLF blocks apoptosis induction by either interleukin (IL)-3 the inactivation of Etv6 in adult mice leads to the selective loss of