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230 Part IV: Molecular and Cellular Hematology Chapter 16: Cell-Cycle Regulation and Hematologic Disorders 231

TABLE 16–3. Common somatic mutations encountered in the major myeloid malignancies. (Continued)
Functional class of Nature of mutation and Approximate Prognostic and/or therapeutic
Gene encoded protein functional consequence incidence implications, if any
CHRONIC MYELOID LEUKEMIA (CML)
BCR-ABL Constitutively active Point mutations that con- 40-90% of cases of “Gatekeeper” T315I mutant inhib-
tyrosine kinase (fusion fer resistance to one or resistance to imatinib ited only by ponatinib
protein) more small molecule TKIs (15% T315I)
c-MYC Oncoprotein Overexpression often due 34% of cases with Genomic instability characteristic
to acquired trisomy 8 clonal evolution of progression to advanced phases
(trisomy 8)
TP53 Master regulator of cell Loss of function often Mutated in 25-30% of Inactivation of tumor suppressor
cycle, DNA damage associated with isochro- patients in myeloid genes characteristic of progres-
response and apoptosis mosome 17 blast phase sion to blast phase
(tumor suppressor)
p16 (INK4A/ARF) Endogenous CDK inhibitor Deletions affect exon 2 Deleted in 50% of Inactivation of tumor suppressor
(tumor suppressor) of locus cases of lymphoid genes characteristic of progres-
blast phase sion to blast phase

this fusion protein (and also the PML Kruppel-like zinc finger [PLZF]- Janus-associated kinase [JAK]–signal transducer and activator of tran-
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RARα fusion derived from the rare t[11;17]) affects cell-cycle control is scription [STAT]). In addition, although there is no direct evidence
its strong interaction with SMRT or N-CoR, two corepressor elements that the abnormal bcr-abl product affects the M checkpoint itself, some
that are important for the recruitment of HDACs, as described below data suggest that bcr-abl–positive CML cells contain elevated MAD2
in “The Role of Histone Deacetylases in Cell-Cycle Regulation.” In and BUB1 levels, proteins that inhibit the APC and therefore cause
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accordance with this is the finding that retrovirally transduced PML- mitotic spindle arrest. Amplification of the fusion sequence is fre-
RARα induces a maturation arrest in the corresponding cells, implying quently used to detect minimal residual disease in patients under ther-
that these cells are unable to express certain transcription factors as a apy with interferon-α, TKIs, and after stem cell transplantation. The
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consequence of the conformational changes caused by the recruitment etv6 gene is the only known non-bcr fusion partner of abl, sometimes
of HDACs. A variant of this chromosomal translocation results in a observed as etv6-abl in ALL or myeloproliferative syndromes (t[9;12]
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fusion protein between RARα and the PLZF protein, which is observed [q34;p13]). The affected cells show only a minor response to imatinib.
in a subset of patients with APL. 195,196 Mutant-activated receptor protein-tyrosine kinases (rPTKs) com-
The translocation t(9:22), which fuses the BCR gene to the c-ABL prise a family of very-well-characterized oncogenes. The constitutive
gene, is a characteristic feature of CML (Chap. 88). The chromosome 9 activation of rPTK usually is achieved by mutations that lead to the
breakpoints, where the c-abl gene is located, involve a large region of dimerization and activation of their cytoplasmic catalytic domains.
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about 200 kb, but fusion genes invariably include the abl exon 2. The Other possible causes of rPTK dimerization are chromosomal translo-
corresponding breakpoints on chromosome 22 are located in a much cations that create chimeric proteins. In the t(2;5) translocation, found
smaller region, including the BCR gene. The bcr-abl fusion protein in several anaplastic large cell lymphomas, N-terminal nucleophosmin
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localizes to the cytoskeleton and displays enhanced tyrosine kinase sequences on the long arm of chromosome 5 are fused to the cytoplas-
activity. It is also found in some cases of ALL and in occasional cases mic domain of the ALK protein on chromosome 2. 207,208 The character-
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of AML. 199,200 Bcr-abl not only regulates cell proliferation, apoptosis, istic translocation of chronic myelomonocytic leukemia, t(5;12), fuses
differentiation, and adhesion, but also induces resistance to cytostatic sequences from the transcription factor TEL to the cytoplasmic domain
drugs by modulation of DNA repair mechanisms, cell-cycle check- of the PDGFRβ (TEL-PDGFβR), resulting in the formation of a TEL-P-
points, and the Bcl-2 family of apoptosis regulators. Upon DNA dam- DGFβR fusion protein and constitutive activation of the receptor tyrosine
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age, bcr-abl enhances repair of DNA lesions and prolongs activation of kinase (RTK), while targeting Id1 (inhibitor of DNA-binding 1)
cell-cycle checkpoints (e.g., G /M), providing more time for repair of inhibits growth of leukemia cells expressing oncogenic FLT3-ITD and
2
otherwise lethal lesions, so that these cells have a significant survival BCR-ABL tyrosine kinases. Patients with the t(5;12) translocation
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advantage. The bcr-abl fusion product is so far the only oncogenic respond to imatinib, as the drug also inhibits the PDGFR. The chro-
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product that is sufficient to induce malignant growth in vivo without mosomal area surrounding the TEL gene is a fragile site, because the
the presence of other abnormal molecular changes. Several reports TEL gene is involved in several other translocations in human acute
have shown that bcr-abl–positive cells display pronounced G /M leukemias (e.g., t[12;9]). One of the TGF-β receptors also is involved
2
delay in response to various chemotherapeutics and irradiation. The in oncogenesis, and mutations are frequently found in colon cancer.
exact mechanism of G /M delay in bcr-abl–positive cells has not been TGF-β receptor signaling acts through the SMAD family of transcrip-
2
characterized in detail, but it seems that the cdc2-cyclin B regulation tion factors.
1
is affected. In addition, bcr-abl, through both kinase-dependent and Two important oncogene families encode the Ras and Rho family
kinase-independent mechanisms, converts p27 kip1 from a nuclear tumor proteins. Ras itself is a G protein, and activating mutations in H-Ras,
suppressor to a cytoplasmic oncogene, which may contribute to bcr-abl K-Ras, and N-Ras have been found in nearly all kinds of human can-
tyrosine kinase inhibitor (TKI)-resistance. The bcr-abl signal trans- cers. Several different Ras mutations are able to transform normal cells
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duction process involves adapter molecules such as GRB2 and GAB2, as in tissue culture. 211,212 Mutations in many different Ras-related pathways
well as signaling pathways (e.g., phosphatidylinositol 3′-kinase [PI3K], have been identified in cancer (e.g., Raf1, p110 PI3K, Rin1, Mekk1),

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