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Chapter 64 Pathobiology of Acute Lymphoblastic Leukemia 1013

MYB Aberrant Growth Factor Signaling
CBP RUNX1
GATA3
TAL1 BCR-ABL1 in B-Cell Acute Lymphoblastic
Leukemia
BRD4
MYB binding motif TAL1 coding sequence The Ph chromosome, which arises from the t(9;22)(q34;q11), was
originally identified in patients with CML; however, it is also found
in about 2% of childhood cases and 20% of adult cases of ALL, which
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are almost always of the precursor B-cell subtype. The t(9;22)
Mediator
Cohesin RNA generates a BCR-ABL1 fusion gene, consisting of 5′ (upstream)
polymerase II sequences from BCR and 3′ (downstream) sequences of ABL1. The
t(9;22) breakpoints on the distal tip of the long arm of chromosome
Fig. 64.4 ONCOGENIC SUPERENHANCER IN T-CELL ACUTE 9 are scattered over a distance of nearly 200 kb within the first intron
LYMPHOBLASTIC LEUKEMIA. Noncoding insertion mutations upstream of the ABL1 proto-oncogene, upstream of the tyrosine kinase
of TAL1 create binding sites for the myeloblastosis (MYB) transcription domain. 295–297 The breakpoints in the BCR gene on chromosome 22
factor, which then recruits it’s H3K27 acetylase binding partner CBP (CREB- cluster in two separate regions of that gene, known as the major
binding protein) leading to the recruitment of core components of a major breakpoint cluster region (M-BCR) or minor breakpoint cluster region
leukemogenic transcriptional complex containing RUNX1, GATA3, and TAL1, (m-BCR). In two-thirds of cases of Ph-positive ALL, the breakpoint
and to the formation of a de novo superenhancer that drives expression of in the BCR gene occurs in the minor breakpoint cluster region
the TAL1 oncogene in a subset of T-cell ALL. (Adapted from Hnisz D, Abraham (m-BCR), but in all cases of CML and about one third of cases of
BJ, Lee TI, et al: Super-enhancers in the control of cell identity and disease. Cell ALL, the breaks occur in the major breakpoint cluster region
155:934, 2013.) 287 298
(M-BCR). The fusion transcript more commonly present in ALL
(m-BCR) encodes a 190-kd protein (p190), whereas the transcript
found in CML and in some cases of ALL (M-BCR) encodes a 210-kd
TAL1 Super-Enhancer Mutations in T-Cell ALL hybrid protein (p210). 299–302 Both types of fusions generate chimeric
oncoproteins that are activated as a tyrosine-specific protein kinase,
Advances in the ability to map transcription factor occupancy and similar to the v-abl protein. 303–305
chromatin modifications genome-wide have revealed the presence The ABL1 tyrosine kinase is localized both in the nucleus and in
of unusually dense clusters of enhancer elements at select genomic the cytoplasm of proliferating cells. It is normally activated by DNA
locations. These elements have been termed super-enhancers (also damage downstream of ATM and appears to promote p53-mediated
stretch enhancers or locus control regions), and are character- growth arrest. 306–309 Mice deficient in Abl1 develop a wasting syn-
ized by dense and broad occupancy by core components of the drome and die soon after birth. 310,311 In contrast to the nuclear and
transcriptional machinery, such as Mediator, as well as histone cytoplasmic distribution of normal ABL1, the BCR-ABL1 fusion
marks associated with active enhancer elements, including H3K27 oncoprotein has a cytoplasmic location and shows increased tyrosine
acetylation. Super-enhancers have been implicated in the expression kinase activity. 312,313 When expressed in murine hematopoietic precur-
of genes responsible for cellular identity in normal and malignant sors, both p190 and p210 transform hematopoietic cells in vitro and
cells. 287–291 induce a syndrome similar to CML in mice. 314–317 Transformation by
Recent work has revealed the presence of focal mutations affecting the BCR-ABL1 oncoprotein involves activation of the RAS- mitogen-
a specific hotspot in a noncoding locus 23 kb upstream of the TAL1 activated protein kinase (MAPK) pathway, PI3K and JUN kinase,
292
oncogene in 5% of T-cell ALL cases. These mutations uniformly c-CBL and CRKL, JAK-STAT, nuclear factor kappa-B (NFκB), SRC,
introduce a binding motif for the MYB transcription factor, and this and cyclin D1. 318–325 The BCR–ABL1 oncoprotein affects multiple
occurs at a locus that already harbors binding motifs for core com- aspects of cell homeostasis, including apoptosis, differentiation,
ponents of the TAL1 complex, including TAL1 itself, RUNX1 and and cell adhesion. An important cellular effect of BCR-ABL1 is
GATA3. These mutations lead to the discovery that the MYB onco- the induction of cellular resistance to DNA damage agents such as
gene is a core component of the TAL1 complex. Indeed, the introduc- cytostatic drugs and irradiation. After DNA damage, BCR-ABL1
tion of this novel MYB binding site is sufficient to recruit the entire extends the duration of the G2/M cell cycle checkpoint and facilitates
TAL1 transcriptional complex to this locus (Fig. 64.4), which leads DNA repair. It also upregulates the antiapoptotic BCLXL gene,
to the generation of an aberrant super-enhancer that drives aberrant contributing to the suppression of apoptotic cell death. 326
overexpression of TAL1 specifically from the mutated allele. 88 The presence of the Ph chromosome has historically been asso-
ciated with an extremely poor prognosis in ALL patients despite
327–329
Duplications of the NOTCH1-Driven Enhancer of treatment with intensified chemotherapeutic regimens. These
patients have been shown to have particularly good responses to
MYC in T-Cell ALL allogeneic BMT in first remission, whether from matched sibling or
from unrelated donors. 330–334 However, the development of imatinib
Aberrant NOTCH1 activation is pathogenic, at least in part, due to mesylate, a pharmacologic tyrosine kinase inhibitor targeting the
NOTCH1-driven overexpression of MYC, as reviewed earlier in this BCR-ABL1 oncoprotein, opened novel therapeutic opportunities for
chapter. Recent work has revealed an enhancer element downstream the management of Ph-positive ALL. The utility of imatinib as a single
of MYC that is highly bound by NOTCH1, and is affected by agent for Ph-positive ALL is limited by the rapid development of
293
recurrent somatic duplications in 3% of human T-cell ALL. This drug resistance. 335,336 However, the combination of BCR-ABL kinase
enhancer forms a looping interaction with the MYC proximal pro- inhibitors with conventional chemotherapy has led to remarkable
moter, and it drives NOTCH1-dependent overexpression of MYC. improvements in outcome for patients with Ph-positive ALL. 337–341
Mice in which this enhancer element has been deleted have a defect Despite its activity, imatinib resistance remains a barrier to
in T-cell development that specifically mimics that seen in mice with further therapeutic improvements in Ph-positive ALL. Resistance
T-cell–specific MYC inactivation. Moreover, murine bone marrow most commonly emerges because of point mutations in the kinase
cells lacking this enhancer element are completely resistant to leuke- domain of BCR-ABL1. As a result, a series of novel BCR-ABL1 kinase
mic transformation by NOTCH1. Finally, duplication of this inhibitors have been developed that retain activity against many
enhancer element drives increased gene expression in a reporter assay, of these mutant oncoproteins. 342–344 Although not all BCR-ABL1
suggesting that this enhancer duplication is pathogenic because it mutations that confer resistance can be overcome with newer agents,
potentiates signaling though the oncogenic NOTCH1-MYC axis. 293,294 the potential of these newer BCR-ABL inhibitors with broader