Page 1157 - Hematology_ Basic Principles and Practice ( PDFDrive )

1016 Part VII Hematologic Malignancies

p53 and CDKN2A mutations inducing aberrant nuclear accumulation of transcriptionally active
NOTCH1. 194
p53 (also known as TP53) is a classic tumor suppressor gene whose
activation induces apoptosis, cell cycle arrest, or senescence in PAX5 and Other B-Cell Developmental
response to distinct stimuli, including DNA damage or aberrant
oncogene activation. 409–411 p53 is mutated or deleted in a wide variety Gene Alterations in Precursor B-Cell Acute
412
of human tumors, and occurs as a heritable cause of cancer in Lymphoblastic Leukemia
families with Li-Fraumeni syndrome. 413–416 p53 is inactivated in
a variety of hematopoietic malignancies, including mature B-cell A high-resolution genome-wide analysis of precursor B-cell ALL cases
ALL, but is mutated or deleted in fewer than 3% of pediatric using single-nucleotide polymorphism arrays identified copy number
precursor B-cell or T-cell ALL cases at diagnosis. 417–419 However, alterations in a number of genes that play important roles in B-cell
435
p53 mutations are seen in approximately 25% of relapsed T-cell development. Genes involved in B-cell development were found to
ALL cases, as well as in association with early treatment failure, be altered by deletion, amplification, mutation, or rearrangement in
suggesting a role for p53 inactivation in the development of resistant 40% of cases of precursor B-cell ALL. The most common abnormali-
disease. 417,418 ties identified were deletions of PAX5. Upon further analysis of other
Despite the rarity of p53 mutations in ALL specimens at the time cases, other mechanisms that led to inactivation of PAX5 were identi-
of diagnosis, the p53 pathway is commonly inactivated by loss-of- fied. These included a number of translocations that led to fusion
function mutations of the CDKN2A locus in ALL. 420–423 CDKN2A proteins that maintained the ability to bind to PAX5 transcriptional
encodes two distinct tumor suppressor proteins, ARF (also known as targets but lost regulatory ability, thus having dominant-negative
p14ARF in humans and p19ARF in mice) and p16INK4a. ARF is activity, and inactivating point mutations that altered the transcrip-
induced by oncogene stress, such as acute MYC overexpression, and tional activity of PAX5. More recently, a recurrent germline PAX5
it binds and sequesters mouse double-minute 2 homolog MDM2, mutation affecting Gly183 in the octapeptide domain of the gene has
leading to p53 activation. p16INK4a is a cyclin-dependent kinase been identified in two unrelated kindreds, thus implicating PAX5 in
436
inhibitor, a family of proteins that also include p15INK4B, an autosomal dominant leukemia predisposition syndrome. Dele-
p18INK4C, p19INK4D, p21, p27, and p57. These constitute a tions were also detected in the TCF3, EBF1, LEF1, IKZF1, and
family of tumor suppressors that negatively regulate the cell cycle by IKZF3 genes, all of which play important roles in B-cell
424
inhibiting CDK phosphorylation of pRB. In particular, human development.
leukemia and lymphoma show a high frequency of 9p21 deletions
involving both the p16INK4A/p14ARF and the p15INK4B loci.
Epigenetic silencing of these tumor suppressor genes through hyper- Ikaros Mutations in High-Risk Precursor B-Cell
methylation of their promoter sequences represents an alternative Acute Lymphoblastic Leukemia
mechanism of gene inactivation. Although p16INK4A/p14ARF and
p15INK4B are homozygously deleted in 20%–30% of precursor Ikaros is a DNA-binding transcription factor that is required for the
B-cell ALL cases and in 70%–80% of T-cell ALL cases, epigenetic development of all lymphoid lineages, and expression of a dominant-
silencing of the p15INK4B promoter has been observed in 44% of negative Ikaros mutation in mice was shown to lead to T-cell lym-
primary B-lineage ALLs. 382,420–422,425–433 phomas. 437,438 However, the role of Ikaros in human leukemias was
not appreciated until genomic analyses of precursor B-cell ALL
FBXW7 and Cyclin C in T-Cell Acute Lymphoblastic patient samples revealed Ikaros (IKZF1) deletions in 29% of pediatric
435
samples. Ikaros deletions are strongly associated with BCR-ABL–
Leukemia positive ALL, and are characteristically acquired at transformation of
423
CML to ALL (lymphoid blast crisis), as well as with Ph-like ALL.
FBXW7 (also known as FBW7) is an E3 ubiquitin ligase that targets Ikaros deletions predict a very high risk of treatment failure that
the transcriptionally active intracellular form of NOTCH1 (ICN), appears to be independent of BCR-ABL1, with patients with Ikaros-
MYC, and cyclin E for degradation, and this gene is inactivated by deleted, BCR-ABL1–negative ALL faring as poor as those with
348
193
mutation or deletion in approximately 10% of T-cell ALL cases. BCR-ABL1–positive ALL. Interestingly, recent work has implicated
In T-cell ALL cell lines, FBXW7 mutation or homozygous deletion mutational activation of a variety of kinases or cytokine receptors in
leads to resistance of NOTCH1 pathway inhibition by γ-secretase Ikaros-deleted, BCR-ABL1–negative ALL, 349,351,439 as reviewed earlier
inhibitor therapy, presumably because intracellular NOTCH1 protein in this chapter. Given the remarkable clinical activity of imatinib in
levels remain high in the absence of FBXW7-mediated degradation high-risk BCR-ABL1 ALL, these findings strongly support the need
despite inhibition of γ-secretase activity. Additionally, tumor-derived for clinical trials testing specific targeted inhibitors for patients with
FBXW7 mutations maintain their ability to bind MYC but do not such targetable oncogenic alterations.
lead to its degradation, and may act as dominant-negative mutants
193
that protect MYC from degradation. FBXW7 also targets the
antiapoptotic protein MCL1 for proteasomal degradation in T-cell Inactivation of LEF1 in T-Cell Acute
ALL, providing an additional oncogenic consequence resulting from Lymphoblastic Leukemia
inactivation of the FBXW7 tumor suppressor. 434
Recent work has implicated cyclin C as a key component of The LEF1 transcription factor, a member of the lymphoid enhancer
the FBXW7-dependent pathway that mediates degradation of binding factor/T-cell specific transcription factor (LEF/TCF) family
194
NOTCH1. Cyclin C, which was originally identified as a growth- of DNA-binding transcription factors, is best known for its role
promoting cyclin, is involved in recurrent heterozygous deletions in as a positive mediator of β-catenin transcriptional activity, a well-
440
human T-cell ALL. In a murine model, loss of one cyclin C allele established oncogene. Recent genomic analyses have identified
accelerates the onset of NOTCH1-induced T-cell ALL, implicating mono- and biallelic deletions and truncating mutations of LEF1 in
this gene as a tumor suppressor. Mechanistically, cyclin C binds 18% of primary T-cell ALL patient samples, unexpectedly implicat-
87
and activates the cyclin-dependent kinases CDK18, CDK8, and ing LEF1 as a T-cell ALL tumor suppressor. LEF1 inactivation is
CDK3 to phosphorylate the intracellular domain of NOTCH1, associated with a very young age at diagnosis, T-cell differentiation
and promote its FBXW7-mediated proteasomal degradation. Thus, arrest at an early cortical stage of T-cell development, and activat-
cyclin C deficiency and FBXW7 are both key components of a ing NOTCH1 mutations. Moreover, T-cell ALL cases with LEF1
degradation pathway that controls physiologic NOTCH1 activity. inactivation are characterized by very high expression of MYC
The model that emerges from these findings is that impaired function mRNA, a surprising finding given that LEF/TCF transcription factors
of either of these tumor suppressors promotes T-cell oncogenesis by transactivate MYC expression when bound to β-catenin. 441,442 In