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CHAPTER 13 GENETIC CONSEQUENCES OF

GENOMIC REARRANGEMENTS
CYTOGENETICS AND Over the past two decades, the genes that are located at the breakpoints
GENETIC ABNORMALITIES of a number of the recurring chromosomal translocations have been
identified. Alterations in the expression of the genes or in the properties
of the encoded proteins resulting from the rearrangement play an inte-
gral role in the process of malignant transformation. The altered genes
1,2
Lucy A. Godley, Madina Sukhanova, Gordana Raca, fall into several functional classes, including tyrosine or serine protein
and Michelle M. Le Beau kinases, cell surface receptors, growth factors and, the largest class, tran-
scription factors. These latter proteins are involved in the induction or
repression of gene transcription, often functioning in a tissue-specific
SUMMARY fashion to regulate cell growth and differentiation.
There are two general mechanisms by which chromosomal
translocations result in altered gene function. The first is deregulation
Cytogenetic and genetic analysis provides pathologists and clinicians with a of gene expression (Chap. 10). This mechanism is characteristic of the
powerful tool for the diagnosis and classification of hematologic malignant translocations in lymphoid neoplasms that involve the immunoglobulin
diseases. The detection of an acquired, somatic mutation establishes the genes in B-lineage tumors and the T-cell receptor genes in T-lineage
diagnosis of a neoplastic disorder and rules out hyperplasia, dysplasia, or tumors. These rearrangements result in the inappropriate or constitu-
morphologic changes from toxic injury or vitamin deficiency. Specific cyto- tive expression of an oncogene. The second mechanism is the encoding
genetic and genetic abnormalities have been identified that are very closely, and expression of a novel fusion protein, resulting from the juxtaposi-
and sometimes uniquely, associated with morphologically distinct subsets tion of coding sequences from two genes that are normally located on
of leukemia or lymphoma, enabling clinicians to predict their clinical course different chromosomes. Such chimeric proteins are “tumor specific” in
and likelihood of responding to particular treatments. The detection of one of that the fusion gene typically does not exist in nonmalignant cells. Thus,
these recurring abnormalities is helpful in establishing the diagnosis and adds the detection of such a fusion gene or protein product can be important
information of prognostic importance. In many cases, the prognostic infor- in diagnosis and in the detection of residual disease or early relapse.
Moreover, they may also be appropriate targets for tumor-specific ther-
mation derived from cytogenetic and genetic analysis is independent of that apies. An example is the chimeric BCR-ABL1 protein resulting from the
provided by other clinical features. Patients with favorable genetic prognostic t(9;22) in chronic myeloid leukemia (CML) (see “Methods of Cell Prep-
features benefit from standard therapies with a well-known spectra of tox- aration” below). All of the translocations cloned to date in the myeloid
icities, whereas those with less-favorable clinical and cytogenetic or genetic leukemias result in a fusion protein.
characteristics may be better treated with more intensive or investigational Chromosomal translocations result in the activation of genes in a
therapies. Pretreatment cytogenetic analysis also can be useful in choosing dominant fashion. A number of human tumors result from homozy-
between post-remission therapies that differ widely in cost, acute and chronic gous, recessive mutations. These mutations lead to the absence of a
morbidity, and effectiveness. The appearance of new abnormalities in the functional protein product, suggesting that these genes function as “sup-
karyotype of a patient under observation often signals clonal evolution and pressor” genes, whose normal role(s) is to limit cellular proliferation.
more aggressive behavior. The disappearance of a chromosomal abnormality The hallmark of tumor suppressor genes is the loss of genetic material in
present at diagnosis is an important indicator of complete remission following malignant cells, resulting from chromosomal loss or deletion, as well as
by other genetic mechanisms (Chap. 10). A subset of tumor suppressor
1
treatment, and its reappearance may herald disease recurrence.
genes act by haploinsufficiency, whereby loss of one allele results in a
reduction in the level of the protein product by half, thereby perturbing
normal cellular processes. This mechanism is common in the recurring
deletions in myeloid neoplasms (Chap. 83).
Acronyms and Abbreviations ALCL, anaplastic large cell lymphoma; ALL, acute Extensive experimental evidence indicates that more than one
lymphocytic or lymphoblastic leukemia; AML, acute myeloid leukemia; AMML, acute mutation is required for the pathogenesis of hematologic malignancies.
myelomonocytic leukemia; APL, acute promyelocytic leukemia; CDS, commonly That is, expression of translocation-specific fusion genes or deregulated
deleted segment; CLL, chronic lymphocytic leukemia; CMA, chromosome microarray expression of oncogenes is required, but insufficient to induce leukemia.
analysis; CML, chronic myeloid leukemia; del, deletion; DLBCL, diffuse large B-cell Thus, an important aspect of leukemia biology is the elucidation of the
lymphoma; EBV, Epstein-Barr virus; FAB, French-American-British; FISH, fluorescence spectrum of chromosomal and molecular mutations that cooperate in
in situ hybridization; FLT3, FMS-like tyrosine kinase; HSC, hematopoietic stem cell; the pathways leading to leukemogenesis. Where known, we describe the
IGH, immunoglobulin heavy chain; inv, inversion; ITD, internal tandem duplication; cooperating mutations associated with specific cytogenetic subsets of
JAK, Janus kinase; LOH, loss of heterozygosity; MALT, mucosa-associated lymphoid leukemia or lymphoma.
tissue; MAPK, mitogen-activated protein kinase; MDS, myelodysplastic syndrome;
Ph, Philadelphia chromosome; PI3K, phosphatidylinositide 3′-kinase; qRT-PCR,
quantitative reverse transcriptase polymerase chain reaction; RA, refractory anemia; METHODS OF CELL PREPARATION
RAEB, refractory anemia with excess blasts; RARα, retinoic acid receptor-α; RARS,
refractory anemia with ring sideroblasts; RARS-t, refractory anemia with ringed Cytogenetic analysis of malignant diseases should be based upon the
sideroblasts and thrombocytosis; RCMD, refractory cytopenia with multilineage dys- study of the tumor cells themselves. In leukemia, the specimen is usu-
plasia; SNP, single nucleotide polymorphism; STAT, signal transducer and activator of ally obtained by marrow aspiration and is typically cultured for 24
transcription; t, translocation; t-, therapy-related, TKI, tyrosine kinase inhibitor; WHO, to 72 hours. When a marrow aspirate cannot be obtained, a marrow
World Health Organization. biopsy (bone core specimen) or a blood sample for patients who have
circulating immature myeloid or lymphoid cells, can often be processed

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