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158 / Chapter 11 Haematological malignancy: aetiology and genetics

2 Overexpression of a normal cellular gene, e.g.

..AGCTCGG.. ..AGTTCGG..
overexpression of BCL - 2 in the t(14; 18) trans-
(a) Point mutation
location of follicular lymphoma or of MYC in
Burkitt lymphoma (Fig. 11.11 ). Interestingly,
this class of translocation nearly always involves
a TCR or immunoglobulin gene locus, presum-
ably as a result of aberrant activity of the
recombinase enzyme which is involved in
(b) Translocation
immunoglobulin or TCR gene rearrangement in
immature B or T cells.
5 5q -
(c) Partial chromosomal deletion
Deletions
Chromosomal deletions may involve a small part of
a chromosome, the short or long arm (e.g. 5q – ) or
the entire chromosome (e.g. monosomy 7). Losses

most commonly affect chromosomes 5, 6, 7, 11, 20
(d) Chromosomal duplication

and Y. The critical event is probably loss of a
tumour - suppressor gene or of a microRNA as in the
Ac Ac 13q14 deletion in CLL (see below). Loss of multiple
methyl
chromosomes is termed hypodiploidy and is seen
..GCGATCA..
Histone frequently in ALL.
DNA
(e) DNA methylation or deacetylation of histones Duplication or a mplifi cation
suppresses gene transcription
In chromosomal duplication (e.g. trisomy 12 in
CLL) or gene amplification, gains are common in

Figure 11.8 Types of genetic abnormality which may chromosomes 8, 12, 19, 21 and Y. Gene amplifi ca-

lead to haemopoietic malignancy. (a) Point mutation; tion is not a common feature in haemopoietic
(b) chromosomal translocation; (c) chromosomal malignancy but has been described involving the
deletion or loss; (d) chromosomal duplication; MLL gene.
(e) DNA methylation or deacetylation of histone
tails suppresses gene transcription.
Epigenetic a lterations

Gene expression in cancer may be dysregulated not
only by structural changes to the genes themselves
but also by alterations in the mechanism by which
whereby they may contribute to malignant change
genes are transcribed. These changes are called

(Fig. 11.9 ).
epigenetic and are stably inherited with each cell
1 Fusion of parts of two genes to generate a division so they are passed on as the malignant cell

chimeric fusion gene that is dysfunctional or divides. The most important mechanisms are methy-
encodes a novel ‘ fusion protein ’ , e.g. CBF/ETO lation of cytosine residues in DNA and enzymatic
in the AML t(8;21) (Fig. 11.10 ), BCR - ABL1 in alterations, such as acetylation or methylation, of
t(9; 22) in CML (see Fig. 14.1 ), RAR α - PML the histone proteins that package DNA within the
in t(15; 17) in acute promyelocytic leukaemia cell (Fig. 11.8 e). Demethylating agents such as aza-
(see Fig. 13.7 ) or TEL - AML1 in t(12; 21) in cytidine increase gene transcription and are valuable
B - ALL. in myelodysplasia (MDS) and AML.