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1018 Part VII Hematologic Malignancies

germline trisomy 21 (Down syndrome) are at increased risk of this revealed that a tumor cell’s sensitivity to mitochondrial apoptosis is
disease. 466,467 Additionally, chromosome 21 is never lost in ALL cases a major determinant of chemotherapy response. Indeed, resistance
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with hypodiploidy, highlighting the role of additional copies of to mitochondrial apoptosis can predict clinical outcome for patients
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chromosome 21 in ALL pathobiology. with a wide range of tumors, including ALL. Investigation of the
In addition to whole-chromosome 21 gains, 1%–2% of precursor dependence of ALL cells on specific antiapoptotic factors revealed that
B-cell ALL cases are characterized by amplification of material from most cases of precursor B-cell ALL and of ETP ALL are dependent
an approximately 5-Mbp region of chromosome 21 that includes on the antiapoptotic BCL2 protein, whereas “typical” T-cell ALL
RUNX1, the so-called intra-chromosomal amplification of chromosome cases are most often dependent on a distinct antiapoptotic protein,
21 (iAMP21). 468,469 Interestingly, iAMP21 is 2700-fold more common BCL-XL. Small-molecule inhibitors of both of these proteins are
in individuals with a germline Robertsonian translocation involving under preclinical development and demonstrate promising activity
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chromosomes 15 and 21. These translocations result in the fusion of in preclinical models. There is considerable interest in the clinical
the long arms of chromosomes 15 and 21 into a single chromosome. application of these antiapoptotic inhibitors for the treatment of
Both of these chromosomes are acrocentric with little genetic material ALL.
on their short arms, thus little genetic material is lost and heterozy-
gous carriers are phenotypically normal. Whole-genome sequencing
analysis of ALL cases with iAMP21 has revealed highly complex NT5C2 Nucleosidase Gene Mutations in Acute
structural and copy number rearrangements within the amplified Lymphoblastic Leukemia
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region. Interestingly, reconstruction of the evolution of this lesion
strongly suggests that the initiating event for this lesion is chro- Genomic analyses of relapsed ALL clinical specimens have revealed
mothripsis, or the shattering of a chromosome in a single catastrophic activating point mutations in the cytosolic 5′-nucleotidase II gene
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event, followed by additional amplification via breakage-fusion- (NT5C2), occurring in approximately 20% of relapsed T-cell ALL
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bridge cycles. These data strongly suggest that the abnormal cases and in 3% of relapsed precursor B-cell ALL. 480,481 NT5C2
structure of the Robertsonian chromosome predisposes it to focal encodes a 5′-nucleotidase enzyme that metabolizes and inactivates
genomic instability involving chromosome 21, possibly because it is nucleoside analog chemotherapeutics, including 6-mercaptopurine
prone to mitotic segregation errors, 472,473 thus providing a potential and 6-thioguanine. Point mutations within NT5C2 lead to increased
mechanism linking germline chromosome 21 Robertsonian translo- enzyme activity in vitro, and their expression is sufficient to induce
cations and iAMP21. Children with iAmp21 ALL are often older at resistance to 6-mercaptopurine and 6-thioguanine in ALL cells.
presentation with a mean age of 9 years and have a low white blood Patients with NT5C2 mutations presented with early relapse, defined
cell count. Several studies have demonstrated increased risk of relapse as within 36 months of achieving remission, and had a uniformly
and overall worse outcomes with this chromosomal aberration; poor prognosis. 480,481 These findings highlight the need for alternative
however, more recent studies have shown improved outcomes with therapeutic strategies for these patients.
intensification of therapy for patients with iAMP21. 474
Until recently, the molecular mechanisms linking trisomy 21 to
B-cell leukemogenesis were unknown. Recent work with a murine Pharmacologic PP2A Activation in T-Cell Acute
model harboring triplication of 31 genes that are orthologous to a Lymphoblastic Leukemia
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segment of chromosome 21q22 revealed that chromosome 21q22
triplication leads to aberrant self-renewal and differentiation arrest of A small-molecule screen in a zebrafish model of MYC-induced T-cell
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B-cell progenitors. Moreover, chromosome 21q22 triplication ALL revealed that perphenazine has activity against zebrafish and
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accelerates the onset of B-ALL induced by either BCR-ABL1 or the human T-cell ALL. Perphenazine is a US Food and Drug
combination of CRLF2 and activated JAK2. Polysomy 21 was found Administration-approved antipsychotic best known as an inhibitor of
to induce loss of the repressive histone mark H3K27 trimethylation, dopaminergic signaling, but its antileukemic activity could not be
indicating suppression of activity of the PRC2. This effect was medi- explained by any of its known molecular targets. Using a mass
ated, at least in part, by overexpression of the histone remodeling spectrometry-based approach, PP2A was identified as a novel target
gene HMGN1, a gene encoded on the triplicated region of chromo- of perphenazine. Perphenazine was found to bind and activate the
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some 21q22. These findings thus formally prove that polysomy 21 phosphatase activity of PP2A, leading to dephosphorylation and
is oncogenic in the B-cell lineage, and provide a molecular mechanism inactivation of several oncoproteins with well-known roles in leuke-
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linking this chromosomal lesion to B-cell pathobiology. mogenesis, including MYC and AKT. Despite its key role as a
tumor suppressor, PP2A-inactivating mutations have not been
CHEMOTHERAPY RESISTANCE MECHANISMS AND described as a recurrent event in T-cell pathobiology. This is likely
because each subunit of PP2A is encoded by multiple redundant
NOVEL THERAPEUTIC TARGETS genes, making it easier for a tumor cell to inactivate PP2A function
by overexpression of a negative regulator, such as the TLX1 onco-
Apoptosis Resistance and Mitochondrial Apoptosis gene. Although the dopaminergic neurotoxicity of perphenazine is
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an obstacle to immediate clinical translation of these findings, the
Despite the clinical application of conventional cytotoxic che- development of more potent and specific PP2A activators could have
motherapy for more than 50 years, the molecular determinants important therapeutic applications for patients with T-cell ALL and
of chemotherapy response have received relatively little attention. other cancers driven by hyperphosphorylated PP2A substrates.
Recent work has implicated a major role for resistance to cell death
through the mitochondrial pathway. The mitochondrial pathway of
apoptosis is regulated by the relative activity of pro- and antiapoptotic FUTURE DIRECTIONS
BCL2 family members, which converge at the mitochondrial outer
membrane. When survival signals predominate, the BAX and BAK1 The immediate applications of the emerging molecular information
effector proteins are in an inactive conformation. However, induc- include a redefinition of risk-classification schemes to emphasize the
tion of mitochondrial apoptosis culminates in the activation of BAX roles of somatically acquired genetic abnormalities that carry a defined
and BAK1, which oligomerize to form pores in the mitochondrial prognosis and likelihood of therapeutic failure. Currently, patients
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outer membrane. This step triggers mitochondrial depolarization, are assigned to treatment according to their initial clinical features
cytochrome c release, and subsequent caspase activation, and is and, increasingly, the genetic and biologic properties of their leukemic
generally considered the point of irreversible commitment to cell cells. We are now in a position to view ALL as a group of heteroge-
death. Recent work using an assay to measure the ability of a fixed neous diseases defined by discrete molecular lesions. As these lesions
proapoptotic stimulus to trigger mitochondrial depolarization has have been systematically analyzed in larger numbers of patients, it