Introduction
Atypical chronic myeloid leukemia (aCML) is a rare
subtype of myelodysplastic/myeloproliferative neoplasm (MDS/MPN)
with an incidence rate of 1–2 cases for every 100 patients with
BCR-ABL1 positive CML (1). In the
World Health Organization (WHO) 2008 classification, aCML is
characterized as ‘peripheral blood leukocytosis due to increased
number of neutrophil and their precursors with prominent
dysgranulopoiesis, with absent/minimal monocytosis or basophilia’
(1). In ~40% of patients, aCML
develops into acute myeloid leukemia with median survival times
ranging between 12 and 29 months. An allogeneic hematopoietic stem
cell transplantation (AlloSCT) is the only option to treat aCML,
which is associated with poor prognoses (1,2).
Chromosomal abnormalities are exhibited by between
20 and 88% of patients with aCML, with +8, i(17q), or −7/−7q
observed most commonly (2).
Additionally, SET binding protein 1 (SETBP1) and ethanolamine
kinase 1 (ETNK1) mutations are associated with aCML, according to
previous studies (3,4). However, no specific recurrent
chromosomal or genetic abnormalities have been identified in aCML
thus far (5). Conversely, X
chromosome abnormalities occur in ~1% of patients with
hematological disorders, with i(X)(p10) considered a recurrent
chromosomal abnormality in hematological malignancies (6).
In the present study, a case of adult aCML with
i(X)(p10) and an additional cytogenetic abnormality appearing 1
year later was described. The cytogenetic abnormalities became
undetectable subsequent to the patient undergoing AlloSCT.
Case report
A 40-year-old female was referred to the Tokyo
Medical and Dental University Hospital (Tokyo, Japan), due to an
annual medical checkup revealing slight leukocytosis and anemia,
with a white blood cell count (WBC) of 12×109/l
(myelocyte, 2%; metamyelocyote, 6%) and a hemoglobin (Hb) level of
9.4 g/dl. A physical examination demonstrated no remarkable
findings. A complete blood count exhibited the following results:
WBC of 8.1×109/l (differential: Blast 0%, promyelocyte
0%, myelocyte 0%, metamyelocyte 7%, neutrophil 56%, lymphocyte 19%,
monocyte 18%), Hb level of 8.6 g/dl, a platelet count of
230×109/l. The bone marrow morphology revealed 4%
blasts, granulocyte proliferation with dysplasia and slight
dysplasia in the megakaryocytic lineage identified by May-Giemsa
staining with Giemsa and May-Grünwald solutions (Muto Pure
Chemicals Co., Ltd., Tokyo, Japan), as presented in Fig. 1.
A G-banded cytogenetic analysis of the bone marrow
cells revealed 46, X, i(X)(p10) in all metaphases analyzed, as
illustrated in Fig. 2A, and
subsequent chromosomal analysis of phytohemagglutinin-stimulated
peripheral blood cells revealed the normal female karyotype 46, XX,
as demonstrated in Fig. 2B.
Fluorescent in situ hybridization (FISH) analysis did not
detect the BCR/ABL fusion gene, and the results of the molecular
genetic analyses were negative for the Janus kinase 2 (JAK2) V617F
mutation, and mutations in granulocyte colony-stimulating factor
receptor (CSF3R), SETBP1, and ETNK1.
The absolute monocyte count of the patient was
>1×109/l, and the percentage of monocytes was
<10%. Furthermore, the percentage of the neutrophil precursors
promyelocytes, myelocytes and metamyelocytes was >10% throughout
the clinical course of the patient. Based on these clinical and
hematological findings, the diagnosis was aCML.
Initially, the patient did not receive any therapy,
but exhibited a rapid increase in WBC to 43×109/l in the
6 months following initial diagnosis, as demonstrated in Fig. 3. Subsequently, hydroxycarbamide
therapy was initiated. However, the treatment did not induce an
adequate hematological response. Furthermore, an additional
cytogenetic abnormality, t(10;17)(p13;q21), was detected in 2/20
bone marrow cells analyzed 1 year following initial diagnosis.
Therefore, the patient received AlloSCT from a human leukocyte
antigen-matched sibling donor. Prior to this, the patient received
3.2 mg/kg/day intravenous busulfan, in 4 doses, between days 5 and
2 prior to AlloSCT treatment, 30 mg/m2/day fludarabine
between days 6 and 2 prior to AlloSCT treatment and total body
irradiation using 400 cGy/day in 2 doses on the day of treatment
initiation. Graft vs. host disease prophylaxis comprised a
continuous infusion of cyclosporine A (2 mg/kg, from 1 day prior to
AlloSCT treatment) and a short course of methotrexate (10
mg/m2 on day 1 following AlloCST treatment, and 7
mg/m2 on days 3 and 6 following AlloCST treatment). The
patient was successfully engrafted with the donor cells on day 20
of transplantation. Post-transplant cytogenetic analysis revealed a
normal male karyotype with full donor chimerism as measured by FISH
analysis, showing the XY pattern in >99% of the bone marrow
cells.
 | Figure 3.Clinical course of the patient. Solid
black line, white blood cells; solid gray line, hemoglobin; dotted
line, immature cells, promyelocytes, myelocytes and metamyelocytes;
dashed line, monocytes; FLU, fludarabine; BU, busulfan; TBI, total
body irradiation; SCT, stem cell transplantation; BMA, bone marrow
aspiration. |
Discussion
Although recurrent chromosomal and genetic
abnormalities are frequently observed, none are specific to aCML
(7). Conversely, a number of genetic
mutations have been reported with diverse frequencies: JAK2V617F at
4–8%; CSF3R at <10%; SETBP1 at 25% and ETNK1 at 8.8%. According
to previous studies, mutations in SETBP1 or ETNK1 are strongly
associated with aCML (3,4,7,8). In the present study, these mutations
were not detected by the direct sequencing methods performed in
previous studies. Therefore, the present case did not demonstrate
the chromosomal abnormalities or genetic mutations previously
reported in aCML (3,4,8).
X chromosome abnormalities occur in ~1% of patients
with hematological disorders (6). At
present, 26 cases with well-characterized i(X)(p10) have been
reported, as demonstrated in Table I
(6,9–12). All
except one of the patients were female. Although the majority of
patients exhibited myeloid malignancies, the present study is the
first case of a patient with aCML exhibiting i(X)(p10) to be
reported to date. It is notable that i(X)(p10) has been
demonstrated to be the sole chromosomal abnormality or the
abnormality in a stem line in ~50% of previously published studies
(6), which suggests that it may serve
an initial or primary role in leukemogenesis. However, detailed
clinical courses of patients with i(X)(p10) have not been
investigated to date. The patient of the present study exhibited
i(X)(p10) as the sole chromosomal abnormality at the point of
diagnosis of aCML, and acquired the additional t(10;17)(p13;q21)
abnormality during the subsequent progression of the disease. This
clinical course is compatible with the hypothesis that i(X)(p10)
may serve a primary role in leukemogenesis. Furthermore,
t(10;17)(p13;q21), which is rare recurrent chromosome abnormality
in myeloid leukemia (13), is
potentially associated with disease progressions such as the
additional cytogenetic abnormalities observed in BCR/ABL-1 positive
CML.
 | Table I.Previously published cases of
hematological malignancies with i(X)(p10). |
Table I.
Previously published cases of
hematological malignancies with i(X)(p10).
| Patient | Age | Gender | Disease | Karyotype | (Refs.) |
|---|
| 1 | 74 | F | AML |
47,X,i(X)(p10),+i(X)(p10)/48,idem,+8/48,idem,+20 | (18) |
| 2 | 79 | F | AML |
47,X,i(X)(p10),+i(X)(p10) | (19) |
| 3 | 76 | F | MDS | 46,X,i(X)(p10) | (20) |
| 4 | 32 | F | CML |
47,XX,t(9;22)(q34;q11),+22,47,X,i(X)(p10),
t(9;22),+22,48,X,i(X)(p10),+i(X)(p10),t(9;22),+22 | (21) |
| 5 | 26 | F | HL |
81-85,XX,-X,i(X)(p10),del(1)(p21),+i(2)(p10)x2, del(3)(q21),del(4)(q?25),i(4)(p10),i(4)(q10),+5,-6,-7,del(7)(q32), i(7)(q10),del(9)(q21q31),der(12)t (3;12)(q21;q22),
−13,-13,-15,+16,del(17)(p11),-18,-18,-20,add(20)(q13), −22,-22,-22,i(22)(q10),+mar | (22) |
| 6 | 75 | F | CMML |
46,X,i(X)(p10)/46,idem,del(20)(q11q13) | (23) |
| 7 | 65 | F | ALL |
47,X,i(X)(p10),add(2)(p?),add(14)(q?),-19,+22,+r/47, idem,del(6)(q?),add(16)
(q24) | (24) |
| 8 | 33 | M | ALL |
46,X,+i(X)(p10),-Y/46,idem,del(17)(p12p13)/46,idem, del(7)(q32q36),del(17) | (25) |
| 9 | 18 | F | HL |
59-83,XXX,-X,i(X)(p10),-1,+2,add(2)(q37)x3,+3,-6, del(7)(q12q22),-8,del(8) (q24),-9,-10,-11,-11,del(11)(q12q13),
+12,-13,-13,-14,-15,-16,-17,-17,-18, add(20)(q13), +del(20)(q11q13),-21,+4mar | (26) |
| 10 | 50 | F | CML |
46,X,i(X)(p10),t(9;22)(q34;q11),i(17) (q10)/50,idem,+1,+8,+13,+19 | (27) |
| 11 | 3 | F | ALL |
48,XX,+i(X)(p10),+21c | (28) |
| 12 | ? | F | CMML | 46,X,i(X)(p10) | (29) |
| 13 | 74 | F | AML | 46, X, i(X)(p10)
[5]/46, XX [7] | (30) |
| 14 | 62 | F | MDS | 46,X,i(X)(p10) | (6) |
| 15 | 62 | F | AML | 46,X,i(X)(p10) |
|
| 16 | 17 | F | ALL | 45,X,-X,r(20)/46,X,i(X)(p10),r(20) |
|
| 17 | 73 | F | MDS |
46,X,i(X)(p10),del(5)(q13q33) |
|
| 18 | 32 | F | AML |
47-50,XX,+i(X)(p10)x2,+8,+9 |
|
| 19 | 49 | F | MDS | 46,X,i(X)(p10) |
|
| 20 | 76 | F | MDS | 46,X,i(X)(p10) or
del(X)(q24)?c |
|
| 21 | 80 | F | MDS | 46,X,i(X)(p10) |
|
| 22 | 38 | F | MDS | 46,X,i(X)(p10) |
|
| 23 | 10 | F | ALL | 52, XX, i(X)(p10),
+4, −7, ins(7;?)(q22;?), t(10;21)(q22;q22), +14, +der(15)t(9;15)(q12;p11.2), +21, +21, mar | (9) |
| 24 | 68 | F | t-AML | 46, XX,
del(20)(q11) [5]/45, X, i(X)(p10),
−7, del(20)(q11) [20] | (10) |
| 25 | ? | F | AML | 46, XX,
inv(3)(q21;q26) [1]/45, idem, −7
[11]/45, idem, i(X)(p10), −1 [8] | (11) |
| 26 | ? | F | CMML | 46, X,
i(X)(p10) | (12) |
| 27 | 40 | F | aCML | 46, XX,
i(X)(p10) | Present case |
Similar characteristics have been observed for
patients exhibiting i(X)(p10) and idic(X)(q13), which is the most
common X chromosome-related abnormality with ~30 cases reported
(14). This abnormality occurs in
females of advanced age (range, 55–87 years) with myeloid
malignancies, including aCML, and is often observed as the sole
abnormality (15). There are also
similar structural abnormalities of the X chromosome in i(X)(p10)
and idic(X)(q13) mutations, with the break points at the centromere
and Xq13, respectively (6). Based on
the clinical and cytogenetic similarities, it is hypothesized that
the mutations may share a common mechanism for leukemogenesis. In
this regard, previous studies have revealed that the gene dosage
effect due to the simultaneous gain of Xp and loss of Xq may serve
a crucial role for idic(X)(q13), which does not result in formation
of a fusion gene (6,14). Notably, the loss of Xq by idic(X)(q13)
and i(X)(p10) results in the deletion of the X-inactive specific
transcript (XIST) gene located at Xq13.2. XIST transcribes the long
non-coding RNA XIST. The transcribed long non-coding RNA spreads
along the X chromosome and serves an important role in the
initiation of X inactivation in female cells. Additionally, there
is considerable evidence that XIST RNA serves other important
functions in the differentiation, proliferation and genome
maintenance of human cells. Furthermore, loss of XIST RNA
expression has been found in female breast, ovarian and cervical
cancer cell lines, thus implicating the dysregulation of XIST in
oncogenesis (16). Notably, a
previous study demonstrated that the deletion of XIST in the
hematopoietic cells in mice results in the development of MDS/MPN
with 100% penetrance (17). Thus, a
loss of XIST may serve a crucial role in the leukemogenesis of
idic(X)(q13) or i(X)(p10) (6,14). Additional genetic and molecular
analyses of i(X)(p10) and idic(X)(q13) in patients with MDS/MPN are
required to establish the association of a loss of XIST with
MDS/MPN in humans.
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