Page 262 - Williams Hematology ( PDFDrive )

236 Part IV: Molecular and Cellular Hematology Chapter 16: Cell-Cycle Regulation and Hematologic Disorders 237

TABLE 16–4. Common somatic mutations encountered in the major lymphoid malignancies.(Continued)
Functional class of encoded Nature of mutation and Approximate Prognostic and/or therapeutic impli-
Gene protein functional consequence incidence cations, if any
TRAF2, BIRC3 BIRC3 is a negative regula- Inactivating or splice site 6% (TRAF2); 10% BIRC3 mutations correlate with del11q;
tor of non-canonical NF-κB mutations (BIRC3) and acti- (BIRC3) both suggest NIK (rather than BCR) sig-
pathway; TRAF2 transduces vating mutations (TRAF2) naling and alternative NF-κB pathway
signals from TNF receptors to lead to enhanced NF-κB activation (resistance to BCR pathway
NF-κB activation inhibitors, e.g., ibrutinib)
TLR2 Toll-like receptor 2 (TLR path- Mutations lead to signifi- Seen only in SOX-
way mediates innate immu- cantly increased produc- 11-/IGHV mutated
nity independent of antigenic tion of IL-6, IL-1RA and IL-8 MCL
stimulation)
NOTCH1/2 Transmembrane receptors, Gain of function mutations 9.5% A subset of tumors with adverse bio-
signaling through which reg- lead to truncated protein logical and clinical features; i.e., blas-
ulates cell death, proliferation that lacks degradation toid morphology and worse survival
and differentiation signals
LARGE GRANULAR LYMPHOCYTIC LEUKEMIA (LGL leukemia)
STAT3 Signal transducer and acti- Activating mutations 40% May correlate with greater preva-
vator of transcription, e.g., lence of neutropenia and rheumatoid
transducing signals from arthritis
cytokine receptor-associated
Janus kinases to the nucleus

and numerous downstream signaling effects of those mutations have is dependent on the extrinsic Fas/CD95 pathway. New data suggest a
also been defined. The Ras and the Rho families of oncoproteins are linkage between c-Myc downregulation, the p16 INK4A /cyclinD1/RB, and
linked by a small G protein called Rac, which is required for transfor- SMAC/Diablo apoptotic pathways. Several different transcription fac-
222
mation by Ras. 213,214 The normal formation of actin filaments is required tors have been implicated in the downregulation of c-Myc expression
for G /S-phase entry. Recent data have shown the Rho-guanosine tri- during differentiation, including CCAAT/enhancer binding protein
1
phosphatases play a key role in the Wnt-signaling pathway, where they (C/EBP) α, CTCF, BLIMP-1, and RFX1. Alterations in the expression
are involved in cellular polarization processes. Thus, alterations in the and/or function of these transcription factors, or of the c-Myc and Max
215
Rho pathway may lead to premature entry into M phase by interfer- interacting proteins, such as MM-1 and Mxi1, can influence the neo-
ence with cytoskeletal organization. The Ras/Raf/MEK/ERK cascade plastic process. 223,224
couples signals from the surface to the intracellular space and triggers Experiments on oncoproteins have focused on apoptosis, the lethal
cell proliferation signals that influence the cell cycle. Abnormal activa- response of a cell to either DNA damage or to signaling through cell
tion of this cascade occurs in several leukemias because of activating surface “death” receptors. Key regulators of apoptosis induced by DNA
mutations in the Ras protooncogene. Ectopic overexpression of Raf damage are the multiple members of the Bcl-2 family of proteins, which
216
proteins is associated with cell proliferation, whereas overexpression of include Bcl-2, Bcl-x , Mcl-1, Bax, Bak, Bim, and Bad, among others.
L
activated Raf is associated with cell-cycle arrest in G phase. 217,218 Differ- Bcl-2 is involved in the t(14;18) chromosomal translocation, which is
1
ent Raf genes have different functions in cells, although A-Raf and B-Raf found classically in follicular lymphoma. The disruption of these loci
225
share three conserved domains termed CR1, CR2, and CR3. A-Raf increases expression of Bcl-2, and results in the uncontrolled accumu-
219
is able to upregulate the expression of cyclin D , cdk2, cyclin E, and lation of malignant B cells, because of an impaired balance between
1
cdk4, whereas B-Raf and Raf-1 induce p21 , leading to a G arrest. 216,219 growth and apoptosis. 226,227 It also has been shown that Bcl-x , Bax, and
cip1
1
L
The mode of action of these Raf molecules is not fully understood but Bad are involved in the regulation of AML cells. For example, the ratio
one explanation why they act differently may be because they activate between Bax and Bcl-2 is a prognostic factor in this myeloid neoplasm.
228
different downstream pathways, namely the MAPK (MEK [MAP/ERK Additionally, Mcl-1 may be even more critical to the development and
(extracellular signal-regulated kinase)]). The three different MAPK cas- maintenance of AML than Bcl-2 or Bcl- . The nuclear HDAC com-
229
XL
cades are the ERK–, c-Jun N-terminal kinase (JNK)/stress-activated plex, which regulates the structural conformation of DNA and therefore
protein kinase (SAPK)–, and p38 pathways. The MAP kinase pathways the activation of several genes, is targeted by ETO, the fusion partner of
consist of three types of kinases in a series, MAPKKK, MAPKK, and the RUNX1 gene in some patients with AML. The t(8;21) translocation
MAPK (ERK), each sequentially activating the next kinase. The MAPK that occurs in such patients allows the formation of a stable complex
cascades all transmit responses from several different surface recep- between the HDAC complex and ETO, contributing to leukemogene-
tors to the nucleus. One explanation for the oncogenic effects of the sis. 230,231 PLZF, PLZF-RARα, and BCL-6 are other oncogenes that target
220
MAPK pathway is that ERK activates c-Myc via phosphorylation on the HDAC complex. 232,233
serine 62. In addition, repression of c-Myc is required for terminal
221
differentiation of many cell types, including hematopoietic cells. Thus, TUMOR-SUPPRESSOR GENES
deregulated expression of c-Myc in both M1 AML cells and in normal
myeloid cells derived from murine marrow blocks terminal differentia- Almost every cancer harbors one or more abnormalities of tumor-sup-
tion and its associated growth arrest, and also induces apoptosis, which pressor genes. These include mutations, translocations, deletions, and

Kaushansky_chapter 16_p0213-0246.indd 237 9/18/15 11:58 PM