K. Pearson 1, M. Groom 1,
M. Atherton 1, S. Turner 1
C. Farmer 1, M. Caswell 2,
A. Douglas 1, P.J. Howard 1
(1) Merseyside and Cheshire Regional
Genetics Laboratories, Liverpool Womenís Hospital, U.K
(2) Department of Haematology, Alder
Hey Hospital, Liverpool, U.K
Presented at the European Chromosome Conference, Vienna, July 1999
Case Report
A female child (10 years) diagnosed in 1994 with typical chronic
myeloid leukaemia (CML), Presented as a classic Ph-Positive CML
and on follow up appeared to be clinically in remission, with further
bone marrow aspirates showing a reduction in the proportion of Ph-Positive
cells detected. Despite a pre-transplant sample showing only normal
cells, in February 1996, after treatment with interferon, the patient
underwent an allogeneic bone marrow transplant. The transplant was
unsuccessful (confirmed by immunophenotyping). Cytogenetic analyses
post transplant showed previously undetected, multiple unrelated
chromosomally abnormal clones but no evidence of the previously
detected Ph-Chromosome (confirmed by Molecular Cytogenetics). Three
years post-transplant this patient remains mildly dysplastic but
otherwise clinically well.
Cytogenetic Results
| Pre
Transplant |
 |
|
26/01/94 |
46,XX,t(9;22)(q34;q11) [30]
|
21/07/94 |
46,XX,t(9;22)(q34;q11) [16]/
46,XX [14]
|
03/11/94
|
46,XX,t(9;22)(q34;q11) [2]/
46,XX [28]
|
23/03/95 |
46,XX [50]
|
Fig 1. MFISH Image and corresponding karyotype from a cell analysed
16/01/98.
click to enlarge above images
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| Post
Transplant |
|
|
|
20/11/96 |
46,X,t(X;4)(q22;p16), add(1)(p1?1), der(14)t(14;?)(q31:?),t(?;15)(?;15),
-15,
+mar [5]/
46,X,t(X;14)(p22;q11), del(11)(q21q23) [2]/
46,XX [33]
|
02/05/97 |
47,XX, -4, add(6)(p11), der(8)t(4;8)(p14;p11), add(22)(q13),
+mar1, +mar2
[2]/
46,XX, -2, -3, ins(9:?)(q22;?), -10, add(12)(p13), -13, del(13)(q12q14),
-16,
+mar3, +mar4, +mar5, +mar6, +mar7 [2]/
46,XX, -4, add(6)(p11), der(8)t(4;8)(p14;p11), add(22)(q13),
+mar1 [cp2]
|
09/10/97
|
47,XX, +mar1 [2]/
47,XX, -4, der(8)t(4;8)(p14;p11), add(22)(q13), +mar1, +mar2
[2]/
46-47,XX, -4 [3],-6 [3],-8 [3], add(22)(q13) [4], mar1 [5],
+mar2 [5],+mar3
[3] [cp7]/
46,XX [3] (see Fig 3)
|
16/01/98 |
46,XX,del(7)(q32) [3]/
46,X,t(X;2)(q22;p13), t(1;9)(p13;q22) [2]/
46,X,-X,del(1)(p22), add(4)(p16),-14,+mar3,+mar4 {2}/
45-47,XX, add(22)(q13) [3],+mar1 [4] [cp7]/
46,XX [5] (see Fig. 1)
|
23/04/98 |
46,del(7)(q32) [1]/
46,X,t(X;2)(q22;q23), t(1;9)(p13;q22) [1]/
46,XX,t(2;11)(p2?3;q1?3) [cp2]/
46,X,t(X;22)(p11;q12), del(1)(q21;q25) [cp2]/
46,XX [8]
|
28/10/98 |
47,XX,-4, der(8)t(4;8)(p14;p11),add(22)(q13), +mar1, +mar2
[5]/
46,X,t(X;2)(q22;q23), t(1;9)(p13;q22) [4]/
46,XX,t(2;11)(p23;q13), del(5)(q14q33), del(13)(q21q31) [2]/
46,XX,t(1;6)(p11;p11), add(12)(p11), del(13)(q21q31) [2]/
46,XX [12]
|
25/02/99 |
44-46,XX,-4 [3], der(8)t(4;8)(p14;p11) [2], add(22)(q13) [4],+mar
[2] [cp4]/
46,XX,t(2;11)(p23;q13), del(5)(q14q33), del(13)(q21q31) [2]/
46,XX,t(5;17)(q35;q11) [2]/
46,XX [11]
|
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Results
Seven follow up samples over two years each
revealed the emergence of subsequent unrelated clones along with
clonal evolution of those previously detected. These Cytogenetic
results were confirmed by M-FISH using the PSI PowerGene M-FISH
Imaging System and the SpectraVysion M-FISH probe kit from Vysis.
The M-FISH technique also revealed certain anomalies undetected
by conventional Cytogenetics including a complex rearrangement involving
chromosomes 1, 14 and 15 (Fig. 2). This patient had only one Leukaemic
cell population and did not undergo clinical transformation during
the course of the disease. Such unrelated clones have been described
in the literature to be uncommon but confer a poor prognosis. Nevertheless
this patient survives 5 years post diagnosis with only mild dysplasia.
The Origin of Unrelated Clones
There are two possible origins for these unrelated clones:
An independent series of mutations, due to bone marrow transplantation
therapy, give rise to the multiple clones with
unrelated chromosome abnormalities which have no clinical significance.
The unrelated clones arise from a multistep process that originates
in a chromosomally normal cell, and the unrelated changes may have
been derived from the common leukaemia clone without chromosomal
changes. The chromosomal abnormalities found are therefore secondary
genetic changes in leukaemogenesis and will lead to relapse to a
secondary leukaemia. (Musilova et al,1996).
Fig 2. Clone undetected cytogenetically.
46,X, t(X;4)(q21;p16), t(1;15)(q43;q21), t(der(1) t(1;15);14) (q31;q32)
[cp3]
Click on image to enlarge
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Fig 3. Karyotype from a cell analysed 09/10/97
Click on image to enlarge
Conclusions
There are two possible conclusions for the prognostic outcome of
this patient:
The abnormalities found represent secondary genetic changes that
are part of a multifactorial leukaemogenesis which
will, sooner or later, manifest as a secondary leukaemia.
The abnormalities found originate in a stem cell damaged during
the treatment. This will eventually become eradicated.
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