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192 / Chapter 14 Chronic myeloid leukaemia

The chronic leukaemias are distinguished from may occur at any age. The diagnosis of CML is
acute leukaemias by their slower progression. rarely difficult and is assisted by the characteristic

Chronic leukaemias can be broadly subdivided into presence of the Philadelphia (Ph) chromosome.

myeloid (Table 14.1 ) and lymphoid groups (see This results from the t(9; 22) (q34; q11) transloca-
Chapter 18 ). tion between chromosomes 9 and 22 as a result of
which part of the oncogene ABL1 is moved to the
Chronic m yeloid ( m yelogenous) BCR gene on chromosome 22 (Fig. 14.1 a) and part

l eukaemia BCR - ABL 1 p ositive of chromosome 22 moves to chromosome 9. Th e
abnormal chromosome 22 is the Ph chromosome.
′
Chronic myeloid leukaemia BCR - ABL1 + (CML) is In the Ph translocation 5 exons of BCR are fused
′
a clonal disorder of a pluripotent stem cell. Th e to the 3 exons of ABL1 (Fig. 14.1 b,c). Th e resulting
disease accounts for around 15% of leukaemias and chimeric BCR - ABL1 gene codes for a fusion protein

of size 210 kDa (p210). This has tyrosine kinase

Table 14.1 Chronic myeloid leukaemia activity in excess of the normal 145 - kDa ABL1
(CML) and myelodysplastic myeloproliferative product. The Ph translocation is also seen in a

neoplasms (see Chapter 16 ).
minority of cases of acute lymphoblastic leukaemia
(ALL) and in some of these the breakpoint in BCR
Type Molecular genetics
occurs in the same region as in CML. However, in
BCR - ABL - 1 > 95% BCR - ABL - 1 p210 other cases the breakpoint in BCR is further
rearrangement < 5% p190 or p230 upstream, in the intron between the first and second

positive CML
exons, leaving only the fi rst BCR exon intact. Th is
BCR - ABL - 1 Various cytogenetic chimeric BCR - ABL1 gene is expressed as a p190
rearrangement abnormalities protein which, like p210, has enhanced tyrosine
negative CML kinase activity.
Chronic neutrophilic Deletions of In most patients the Ph chromosome is seen by
leukaemia chromosome 20q and karyotypic examination of tumour cells (Fig. 14.1 d)
trisomy 21 or 9 in but in a few the Ph abnormality cannot be seen
some under the microscope but the same molecular rear-
rangement is detectable by more sensitive tech-

Chronic eosinophilic FIPILI – PDGFR - α (in
leukaemia those who respond to niques: fl uorescence in situ hybridization (FISH)
imatinib) generated by (Fig. 14.1 e) or polymerase chain reaction (PCR).
interstitial deletion on Ph - negative BCR - ABL1 positive CML behaves clin-
chromosome 4q12 ically like Ph - positive CML. As the Ph chromosome
is an acquired abnormality of haemopoietic
Chronic monocytic Very rare
leukaemia stem cells it is found in cells of both the myeloid
(granulocytic, erythroid and megakaryocytic) and
Chronic PDGFR - β rearrangement

lymphoid (B and T cell) lineages. Ph – , BCR -
myelomonocytic in a minority who
ABL1 – chronic myeloid leukaemia is classifi ed with
leukaemia respond to imatinib
the myelodysplastic/myeloproliferative syndromes
Juvenile 30% PTPN11 (encodes (see Chapter 16 ).
myelomonocytic SHP - 2 ) mutations
leukaemia 20% K - RAS or N - RAS
mutations Clinical f eatures
10% NF1 mutation

This disease occurs in either sex (male : female ratio
Refractory anaemia Somatic mutations of of 1.4 : 1), most frequently between the ages of 40
with ringed JAK2 and MPL and 60 years. However, it may occur in children and
sideroblasts and
neonates, and in the very old. In most cases there
thrombocytosis
are no predisposing factors but the incidence was