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Chapter 64 Pathobiology of Acute Lymphoblastic Leukemia 1011

optimal strategy for clinical application of NOTCH1 and PI3K binds unmethylated DNA, four plant homeodomain zinc fingers
inhibition in patients with T-cell ALL. with an embedded bromodomain, and a transcriptional repression
228
C
Recent work has also revealed that some T-cell ALL cases in which domain. The C-terminal fragment MLL contains a transcriptional
the bulk cell population is sensitive to NOTCH1 inhibition harbor activation domain that recruits the histone acetyltransferase cAMP
minor populations of so-called “persister” cells that are resistant to response element-binding protein (CBP) and a SET domain that is
NOTCH1 inhibitors. This “persister” state is not driven by genetic responsible for its histone 3 lysine 4 (H3K4) methyltransferase
mutations, but is instead a reversible cellular state characterized by activity. 235
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chromatin compaction. These NOTCH1 inhibitor-resistant cells Wild-type MLL encodes a H3K4 lysine methyltransferase, and
maintain expression of MYC, a crucial downstream target of H3K4 methylation is associated with transcriptional activation. Strik-
NOTCH1, despite effective inhibition of NOTCH1 activity. 213,214 ingly, the H3K4 methyltransferase domain is invariably lost in MLL
However, the survival of these cells is specifically dependent on fusion oncoproteins. MLL fusion oncogenes result from transloca-
BRD4, 213,214 a transcriptional regulator whose ability to bind acety- tions whose breakpoints cluster between exons 5 and 11 of MLL, and
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lated chromatin can be specifically inhibited using small molecules. the resultant fusion proteins retain the N-terminal region of MLL,
Combination therapy with inhibitors of both BRD4 and NOTCH1 including the AT-hook and CxxC domains that bind DNA in a
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can block emergence of this resistance mechanism, and this approach sequence-nonspecific manner. By contrast, the C-terminal domains
has promising in vivo activity in preclinical models. 213,214 that mediate the association of wild-type MLL with its endogenous
chromatin remodeling complex and its H3K4 methyltransferase
MYC Mutations in Mature B-Cell activity are invariably lost from oncogenic MLL fusion proteins.
Instead, the C-terminus of MLL fusion proteins is provided by one
Lymphoblastic Leukemia of more than 60 different translocation partners, with common
translocations such as the t(4;11), t(9;11), and t(11;19)(q23;p13.3)
As reviewed previously in this chapter, mature B-cell ALL is charac- resulting in the in-frame fusion of MLL to AF4, AF9, and ENL,
terized by chromosomal translocations that place the MYC coding respectively. The unrelated t(11;19)(q23;p13.1) translocation results
sequence under the control of Ig gene-regulatory elements. Although in fusion of MLL to ELL, the RNA polymerase II elongation
the MYC coding region is not structurally altered by these transloca- factor. 237,238
tions in most cases, point mutations of MYC commonly arise in these Formal proof that MLL fusions play a critical role in the develop-
tumors at codons 58 or 62. 216–218 These codons encode phosphoryla- ment of leukemias has come from the generation of murine models
tion sites that regulate the activity and proteasomal degradation of of MLL-induced leukemias. Chimeric mice harboring a MLL-AF9
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MYC. These mutations lead not only to the aberrant stabilization fusion gene generated by homologous recombination developed
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of MYC protein, 220–222 but also inhibit the ability of MYC to activate leukemias with a latency of 4–12 months. Retroviral transduction
apoptosis, while its ability to stimulate proliferation remains intact. 223 of MLL-ENL, MLL-ELL, and MLL-CBP fusion genes in hematopoi-
etic precursors induces transformation upon transplantation into
recipient mice. 240–242 Similar results were obtained with a model in
Mutations of Histone-Modifying Enzymes which chromosomal translocations involving the MLL locus are
induced by directed interchromosomal recombination in mice, a
DNA exists in cells in complex with histone proteins and other strategy that experimentally reproduces the initiating events in the
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molecules in a complex known as chromatin. Posttranslational modi- pathogenesis of MLL-rearranged leukemias. Interestingly, the
fications of histone proteins play prominent roles in the regulation introduction of MLL-AF9 into committed granulocyte-macrophage
of chromatin structure. Chromatin structure at individual loci can be progenitors in the mouse leads to the reactivation of a subset of genes
broadly categorized as euchromatin, or “open” chromatin, where normally expressed only in HSCs, and transforms these committed
transcription factor binding sites in DNA are readily accessible to the precursors into AML leukemic stem cells by imparting the properties
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transcriptional machinery, or heterochromatin, where chromatin is of self-renewal, suggesting that the leukemogenic lesion in MLL-
compacted and DNA is generally not accessible to the transcriptional rearranged leukemia might occur in a committed progenitor rather
machinery. Alternations in chromatin structure can have profound than in a pluripotent HSC.
effects on the gene expression program activated by transcription MLL-rearranged B-lineage leukemias have a characteristic
factors. Several enzymes that catalyze covalent histone modifications gene-expression signature that includes the upregulation of several
are recurrently mutated in ALL, highlighting a central role for dys- HOX genes and the expression of numerous myeloid markers. 245–247
regulation of chromatin structure in human leukemogenesis. Both early B- and T-cell ALLs with MLL rearrangements showed
a characteristic upregulation of specific HOX genes, including
HOXA9, HOXA10, and HOXC6, and the HOX gene regulator
MLL Fusion Genes MEIS1. 245–247 These results, together with the demonstration that
HOXA9 plays important roles in the transformation of hemato-
Translocations involving the MLL gene (also known as KMT2A) on poietic precursors by MLL fusion oncogenes in murine leukemia
chromosome 11q23 occur in approximately 80% of infant ALL cases, models, 248,249 emphasize the central role of HOX gene dysregulation
5% of AML cases, and 85% of secondary AML cases that occur in in the pathogenesis of MLL-rearranged leukemias. Additionally, as
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patients treated with topoisomerase II inhibitors. MLL is the discussed later in this chapter, overexpression or activating mutations
human ortholog of the Drosophila trithorax gene. 224–227 Trithorax of the FLT3 receptor tyrosine kinase are frequent in MLL-rearranged
proteins are positive regulators of homeobox gene expression and act leukemias. 245,246,250,251
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antagonistically to polycomb proteins. Wild-type MLL positively Until recently, the precise mechanisms mediating the oncogenic
regulates HOX gene expression and is required for both primitive and activity of MLL fusion proteins were unclear, because MLL transloca-
definitive hematopoiesis. 229–231 Wild-type MLL is a member of a large tion partners have no sequence similarity. However, recent work has
transcriptional regulatory complex, together with histone deacetylases shown that several distinct MLL translocation partners are function-
and members of the SWI/SNF chromatin-remodeling complex. 232 ally linked through their association in protein complexes that regulate
252
The MLL protein undergoes proteolytic processing by Taspase1, transcriptional elongation (Fig. 64.3). Oncogenic MLL fusion
a specialized protease that cleaves the MLL protein into N-terminal proteins have been implicated in the DOT1L, SEC, and PAFc
N
C
(MLL ) and C-terminal (MLL ) fragments that remain associated transcriptional complexes. The DOT1L complex consists of DOT1L,
through intramolecular protein–protein interaction domains. 233–235 a H3K79 methyltransferase, and multiple MLL fusion partners,
N
MLL contains several DNA-binding domains, including AT-hook including AF9, ENL, and AF10. 253–258 The SEC (also known as
domains that nonspecifically bind the minor groove of DNA, a p-TEFb or AEP) complex consists of a CDK9 and cyclin T heterodi-
methyltransferase homology region (CxxC domain) that specifically mer (known as p-TEFb) that phosphorylates RNA polymerase II,