Page 1155 - Hematology_ Basic Principles and Practice ( PDFDrive )

1014 Part VII Hematologic Malignancies

specificity to further improve outcomes is actively being investigated. cytometry, and were strongly associated with the presence of the
Additionally, a novel pathway mediating resistance to BCR-ABL1 TCF3-PBX1 rearrangement or 6q21 deletion, but rare in other ALL
inhibition has been uncovered in Ph-positive ALL. Upon BCR-ABL1 subsets. 353,354 Interestingly, the oncogenic TCF3-PBX1 translocation
inhibition, these cells markedly upregulate expression of the BCL6 itself directly binds and upregulates genes encoding key components
353
transcription factor, a well-known oncogene that is often translocated of the B-cell receptor in these cases. Active B-cell receptor signaling
345
in diffuse large B-cell lymphomas. BCL6 then blocks activation leads to downstream activation of SRC, SYK, and PI3K oncogenic
of the p53 pathway via transcriptional repression of ARF and thus signaling pathways. Importantly, these cases are sensitive to small-
blocks the therapeutic efficacy of monotherapy with imatinib in molecule inhibitors of kinases that mediate B-cell receptor signaling
Ph-positive ALL cells. Importantly, inhibition of BCL6 activity in preclinical models, thus providing a novel potential therapeutic
genetically or using a peptide inhibitor of BCL6 has demonstrated strategy for these patients. 353,354
marked activity in patient-derived BCR-ABL1 xenografts grown in
immunodeficient mice, highlighting the therapeutic relevance of
these findings. 346 RAS Gene Mutations

Pioneering studies into the molecular etiology of cancer led to the
BCR-ABL1–Like Acute Lymphoblastic Leukemia identification of activated homologs of either HRAS or KRAS in
human tumor DNA. 355,356 These proto-oncogenes were originally
Analysis of the gene expression signatures of patients with ALL has identified on the basis of their homology with viral oncogenes. Gene-
led to the identification of a new subtype of precursor B-cell ALL, transfer methods identified an additional member of the RAS gene
termed BCR-ABL1–like or Ph chromosome-like (Ph-like) ALL. These family, called NRAS, 357,358 that had not been observed as a component
cases were identified because they lack BCR-ABL1 translocations, yet of a transforming retrovirus. Proto-oncogenes of the RAS family
are characterized by a gene expression signature nearly identical to (HRAS, KRAS, and NRAS) encode 21-kDa proteins that are associ-
that of BCR-ABL1-positive ALL. These patients are at very high risk ated with the inner surface of the cytoplasmic membrane and are
359
of treatment failure, mirroring the poor prognosis of BCR-ABL1 involved in growth factor receptor signaling. RAS proteins are
ALL. 347,348 One common genetic feature common to both BCR-ABL guanosine nucleotide-binding proteins (G proteins) that are GTP-
and BCR-ABL–like ALL is the deletion of the Ikaros tumor suppres- bound in their active form and GDP-bound in their inactive form.
348
sor. However, in-depth genomic investigation of BCR-ABL1–like The RAS proto-oncogenes are converted to the status of transforming
ALL has also revealed that most of these cases harbor chromosomal oncogenes by somatic mutations that most commonly alter the
translocations or point mutations leading to dysregulated activation amino acids specified by codons 12, 13, or 61. Mutated RAS genes
of growth factor signaling pathways. These include activating trans- lose their intrinsic GTPase activity, thus accumulating in their active,
locations of the ABL1 kinase to “noncanonical” fusion partners, of GTP-bound conformation, even in the absence of growth factor
the cytokine receptor CRLF2 or the erythropoietin receptor EPOR, binding to surface receptors. Aberrant RAS-mediated signaling con-
or activating mutations of the RAS or JAK-STAT pathways. 349–351 tributes to transformation through activation of the PI3K and MAPK
These findings have important clinical implications, as many of these pathways. 359
mutated genes are targetable with clinically relevant inhibitors, and In ALL, mutations of codons 12, 13, or 61 of NRAS have been
clinical trials testing specific targeted agents in genetically defined found in approximately 10% of patients, while KRAS mutations have
subsets of the disease are underway. been identified in 5%–10% of patients. 360,361 RAS mutations are
considerably more common in specific molecular subsets of ALL. Up
NUP214-ABL1 in T-Cell Acute Lymphoblastic to 50% of cases of MLL-rearranged ALL harbor mutations of NRAS
361,362,363
although these mutations can be subclonal and lost
or KRAS,
Leukemia at relapse. RAS mutations have also been identified in approxi-
363
mately 30% of Down syndrome-associated precursor B-cell ALL and
364
Although the BCR-ABL1 translocation is rare in T-cell ALL, ampli- appear to be mutually exclusive of JAK2 mutations in this setting.
fied episomes containing NUP214-ABL1 fusion genes have recently RAS mutations appear to be more frequently found in the setting of
been described in approximately 6% of children and adults with relapsed ALL and are associated with a poor prognosis in this
352
365
T-cell ALL. These episomes appear to arise via a mechanism in setting. The development of an effective pharmacologic approach
366
which the genomic region of chromosome 9q34, which contains both for direct inhibition of RAS has been elusive. However, recent
the NUP214 and ABL1 genes, is circularized in a manner that leads studies in preclinical models of RAS-driven ALL have revealed the
to the fusion of these two genes. The breakpoint in the ABL1 gene therapeutic potential of inhibitors of key downstream effectors of
in all of these cases occurs in intron 1, which is the same breakpoint RAS signaling in ALL, including MEK and PI3K, thus providing a
observed in Ph-positive CML and precursor B-cell ALL, but the rationale for clinical trials testing such an approach for RAS-mutant
NUP214 breakpoints are variable. The wild-type NUP214 protein is ALL. 365,367,368
a component of the nuclear pore complex and may contribute
oligomerization motifs to the NUP214-ABL1 fusion oncogene. The
NUP214-ABL1 fusion protein has constitutively activated ABL1 PTEN-PI3K-AKT Mutations in T-Cell Acute
tyrosine kinase activity, which is inhibited by the BCR-ABL kinase Lymphoblastic Leukemia
352
inhibitor imatinib. The therapeutic potential of imatinib or
second-generation tyrosine kinase inhibitors for NUP214-ABL1– The PI3K-AKT signal transduction pathway, which is negatively
positive T-cell ALL is of considerable interest. regulated by the PTEN tumor suppressor, induces cellular growth
and proliferation while inhibiting apoptosis and is aberrantly acti-
369–371
B-Cell Receptor Signaling in Acute Lymphoblastic vated in a range of human cancers. In T-cell ALL, recent work
has identified a very high frequency of mutational activation of
Leukemia oncogenic signaling through this pathway, most often via deletions
or truncating mutations of PTEN, but activating mutations of PI3K
Despite its importance in the molecular pathogenesis of mature B-cell and AKT genes also occur. 209,210,372,373 Moreover, deletions of PTEN
lymphomas, the role of B-cell receptor signaling in ALL was poorly have been found to predict treatment resistance in clinical speci-
understood. However, a recent study has revealed that 10%–15% of mens. 40,209 Studies in zebrafish and patient-derived xenograft mouse
cases of ALL are characterized by active signaling through the B-cell models have identified that acquisition of the PI3K-AKT pathway
353
receptor. Such B-cell receptor-positive cases were identifiable by during clonal evolution of leukemic blasts leads to primary glucocor-
expression of the Ig µ heavy chain or of BCL6 protein on flow ticoid resistance, an effect mediated by direct phosphorylation of the