ORIGINAL ARTICLE

Cytogenetic profile of 1,863 Ph/BCR-ABL-positive chronicmyelogenous leukemia patients from the Chinese population

Qitian Mu & Qiuling Ma & Yungui Wang & Zhimei Chen &

Xiangmin Tong & Fei-Fei Chen & Ying Lu & Jie Jin

Received: 12 December 2011 /Accepted: 28 January 2012 /Published online: 15 February 2012# Springer-Verlag 2012

Abstract Cytogenetic analyses of chronic myelogenousleukemia (CML) have been performed previously in a largenumber of reports, but systematical research based on largesample sizes from the Chinese population is seldom avail-able. In this study, we analyzed the cytogenetic profiles of1,863 Philadelphia (Ph)/BCR-ABL-positive CML patientsfrom a research center in China. Of 1,266 newly diagnosedCML patients, the median age was 41 years, which is youngerthan the median age of diagnosis in western populations. Theincidence of additional chromosome abnormalities (ACA)was 3.1% in newly diagnosed chronic phase (CP), 9.1% inCP after therapy, 35.4% in accelerated phase, and 52.9% inblast crisis (BC), reflecting cytogenetic evolution with CMLprogression. A higher prevalence of ACA was observed invariant Ph translocations than in standard t(9;22) in the diseaseprogression, especially in BC (88.2% vs. 50%, P00.002).Moreover, a hyperdiploid karyotype and trisomy 8were close-ly correlated with myeloid BC, while a hypodiploid karyotypeand monosomy 7 were associated with lymphoid-BC. Amongsubsets of myeloid-BC, myeloid-BC with minimal

differentiation had a higher ACA rate than myeloid-BC withgranulocytic differentiation (80% vs. 46.8%, P00.009) andmyeloid-BC with monocytic differentiation (80% vs. 42.9%,P00.006). These data provide novel insights into cytogeneticsof CML within the Chinese population.

Keywords Chronic myelogenous leukemia . Cytogenetics .

Additional chromosome abnormalities . Variant Phtranslocation . Blast crisis

Introduction

Chronic myeloid leukemia (CML) is a myeloproliferativedisorder characterized by the balanced chromosomal trans-location t(9;22)(q34;q11) [1], resulting in Philadelphia (Ph)chromosome and the BCR/ABL fusion gene which plays apivotal role in the pathogenesis of CML [2, 3]. Most CMLpatients progress through three distinct clinical phases:chronic phases (CP), accelerated phases (AP), and blastcrisis (BC). Generally, CML patients are in CP for severalyears and then evolve into AP or BC [4]. Morphologicallyand immunophenotypically, myeloid transformationaccounts for approximately 70% of CML cases, while lym-phoid transformation accounts for 30% [5]. In the course ofthe disease, additional chromosome abnormalities (ACA)including trisomy 8, duplication of the Ph chromosome,isochromosome 17q [i(17)(q10)], trisomy 19, and trisomy21 appear gradually [6, 7]. Among these ACA, trisomy 8,acquisition of an additional Ph chromosome, and i(17q) havemore tendency to myeloid transformation than lymphoidtransformation [5, 8, 9]. Moreover, some ACA such as lossof Y indicate poor response to imatinib therapy [10].

Many currently published studies, most of which werebased on western populations, have looked at cytogeneticfeatures during the transition from CP into BC and their

Qitian Mu and Qiuling Ma contributed equally to this work.

Q. Mu :Q. Ma :Y. Wang : Z. Chen :X. Tong : F.-F. Chen :J. Jin (*)Department of Hematology & Institute of Hematology, The FirstAffiliated Hospital, Zhejiang University School of Medicine,No.79 Qingchun Road,Hangzhou 310003 Zhejiang, People’s Republic of Chinae-mail: zjuhematology@163.com

Q. Mu :Y. LuNingbo First Hospital,Ningbo 315010 Zhejiang, People’s Republic of China

Q. MaDepartment of Hematology, The Second Affiliated Hospitalof Henan College of Traditional Chinese Medicine,No. 6 Dongfeng Road,Zhengzhou 450002 Henan, People’s Republic of China

Ann Hematol (2012) 91:1065–1072DOI 10.1007/s00277-012-1421-6

relationship to phenotypes of CML-BC. The majority ofthese studies, however, seldom focused on the geographicheterogeneity of cytogenetic abnormalities and the associa-tion between ACA and variant Ph translocations in CML. Inthis systematic study, cytogenetic data of 1,863 CMLpatients, most of whom were from Zhejiang, a southeasternprovince of China, were analyzed to reveal cytogeneticdiscrepancies in CML between Chinese and western popu-lations and to further discover the correlation between cyto-genetic patterns and cell morphology in CML-BC.

Design and methods

Patients

One thousand eight hundred sixty-three CML patients' in-formation was obtained from the Institute of Hematology,The First Affiliated Hospital, Zhejiang University Collegeof Medicine from 1995 to 2010. As the central hospital inZhejiang Province, the majority of local hematologicalpatients had cytogenetic analyses performed in our institu-tion as previously described [11]. In this cohort, 837 patientshad 2 to 17 karyotypic analyses sequentially performed. Thediagnoses of the three phases of CML are distinguished bythe blast percentage in peripheral blood (PB) or bone mar-row as follows: <10% for CP, 10% to 19% for AP, and≥20% for BC. CML-CP patients were divided into newlydiagnosed CP group (before treatment) and CP after therapygroup (CML-CP patients not having acquired major cytoge-netic response via treatment). The types of CML-BC weredistinguished by morphological analysis and by immunolog-ical tests using flow cytometry. Of 1,863 CML patients, 39were treated with interferon alpha (INF-α) combination withhydroxyurea (HU); 27 received INF-α combination with HU,followed by tyrosine kinase inhibitors; 89 were treated withHU, followed by tyrosine kinase inhibitors in late stage of thedisease; 341 were treated with tyrosine kinase inhibitors inearly stage of the disease; 91 underwent allogeneic (allo) andautologous (auto) marrow transplantation (BMT); and therests were mainly treated with HU. The majority of patientsin AP or BC received chemotherapy. The study was approvedby the Medical Ethical Committee of the First AffiliatedHospital, Zhejiang University College of Medicine.

Cytogenetic analyses of CML patients

Chromosomes were prepared from 24-h unstimulated cul-ture of bone marrow cells, and chromosomal analysis wasperformed using conventional R-banding technique. Finalkaryotypic results were described according to the Interna-tional System for Human Cytogenetic Nomenclature 2009.Fixed cells prepared from bone marrow samples were used

for FISH studies. LSI bcr/abl dual color translocation probeswere supplied by Abbott Molecular/Vysis (Des Plaines, IL,USA). Denaturation of probes, hybridization, and post-hybridization washes were performed according to the man-ufacturer's instructions. Detection was conducted by usingthe Olympus BX51 fluorescence microscope.

Statistics

Pearson's correlation was performed to analyze associationsbetween cytogenetic characteristics and subsets of CML-BCand to compare ACA of the variant Ph translocations to thatof the standard t(9;22). P values <0.05 were consideredstatistically significant. Statistical analyses were evaluatedusing SPSS 16.0 software (SPSS Inc., Chicago, IL, USA).

Results

Cytogenetic features and age and gender distributionof newly diagnosed CML patients

In this series, of 1,266 newly diagnosed CML patients, 15(1.18%) had no metaphases, 1,174 (93.9%) had the standardt(9;22), and 59 (4.7%) had variant Ph translocations. Theremaining 18 (1.4%) harbored normal karyotypes or otherchromosome abnormalities not involving chromosome 9and chromosome 22, but contained a positive BCR-ABLgene rearrangement as demonstrated by FISH or RT-PCR.CML-CP and CML-AP patients were seen in 1,246 (98.4%)and 20 (1.6%), respectively.

CML occurred in all ages, with an age peak of incidence at30–49 years. The median age was 41 years (41 years in malesand 42 years in females), ranging from 6 months to 87 years.The male-to-female ratio of CML was 1.66:1 (Fig. 1).

Variant Ph translocation in CML

In our 1,863 CML patients, 99 (5.3%) had a variant Pharrangement. Among these, 96 were three-way variant Ph

Fig. 1 Age and gender distribution of newly diagnosed CML patientswith Ph/BCR-ABL positive. The ratio of male to female was 1.6:1

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arrangements and 3 were four-way variant Ph arrangements.All chromosomes except 13, X, and Y participated in varianttranslocations. Among the chromosomes involved, chromo-somes 1 and 12 were the most common, both accounting forabout 13.7%. The most frequently occurring breakpoints were1q21, 12q24, 7q22, 15p11, and 19q13 (Fig. 2). Variant Phtranslocations occurred in 59 patients (59.6%) with newlydiagnosed CML and in 22 patients (22.2%) with progression.In the remaining 18 cases, it was unclear when the variant Phtranslocations formed due to lack of sequential karyotypes.

Additional chromosome abnormalities in different phases ofCML

In our cohort, ACA were detected in all phases of CML-CPincluding newly diagnosed CML-CP. The ACA rate in eachphase, however, was obviously different. The lowest inci-dence was newly diagnosed CP (3.1%), followed by CP aftertherapy (9.1%), AP (35.4%), and BC (52.9%) (Table 1),which reflected the increasing trend of ACA accompanyingdisease progression. Moreover, the ACA rate in variant Phcases was higher than that in standard t(9;22) cases in all

phases, among which, significant differences were observedin CP after therapy (P00.017) and in BC (P00.002) (Table 2).

ACA included numerical abnormalities and structuralabnormalities. Among numerical abnormalities, hyperdi-ploid incidence was significantly higher than hypodiploidin all phases except newly diagnosed CP. Additional copiesof the Ph chromosome and trisomy 8 were the most frequentcontributors to hyperdiploid karyotypes. Loss of 17p, in-cluding chromosome deletion and isochromosome forma-tion, was one of the most common structural abnormalities.The comparatively frequent ACA in different phases werelisted in Table 1.

Chromosomal aberrations in relation to cell morphology inBC

Of 223 CML-BC patients, lymphoid-BC and myeloid-BCwere observed in 58 (28.6%) and in 140 (69.0%) cases,respectively. The remaining 25 cases cannot be classified.Among the myeloid-BC patients, granulocytic, monocytic,and minimal differentiation were frequent, granulo-monocytic and erythroid differentiation were less common

Fig. 2 Chromosome locus involved in breakpoints of the variant t(9;22) translocations. Diamonds: enumerating the number of cases atlocus. Ninety-six CML patients with three chromosomes being

involved in the variant translocation and three CML patients with fourchromosomes being involved in the t(v;22): in total, 102 breakpoints inaddition to the standard breakpoints

Ann Hematol (2012) 91:1065–1072 1067

(Table 4), and megakaryocytic differentiation was rare, seenin only one case.

Pearson's correlation was conducted to identify correlationsbetween karyotypic abnormalities and phenotype of CML-BCpatients. Our results revealed that there was significant differ-ence in the total ACA rate between myeloid-BC patients andlymphoid-BC patients. However, the rate of myeloid-BC withhyperdiploid karyotypes (n038, 27.1%) was significantlyhigher than that of lymphoid-BC patients with hyperdiploidkaryotypes (n08, 13.8%; P00.043). The opposite result wasobserved in CML-BC patients with hypodiploid karyotypes(P00.01). These patients had a lower rate of myeloid-BC (n011, 7.9%) and a higher rate of lymphoid-BC (n012, 20.7%).Trisomy 8 was closely associated with myeloid-BC patients(n021, 15% in myeloid-BC patients; n02, 3.4% in lymphoid-BC patients; P00.021). Although additional copies of the Ph

chromosome, loss of 17p (n015, 10.7% in myeloid-BCpatients; n02, 3.4% in lymphoid-BC patients), trisomy 19(n08, 5.7% in myeloid-BC patients; n01, 1.7% inlymphoid-BC patients), and trisomy 21 (n09, 6.4% inmyeloid-BC patients; n00 in lymphoid-BC patients) weremore frequently observed in myeloid-BC patients, no signif-icant differences were observed. Monosomy 7 was the onlyindividual chromosome abnormality which was more oftenencountered in lymphoid-BC (n07, 12.1%) than in myeloid-BC patients (n02, 1.4%, P00.004) (Table 3).

Correlation between chromosomal aberrations and cellmorphology of myeloid-BC

To further elucidate the correlation between cytogenetics andcell morphology of myeloid-BC, we analyzed chromosome

Table 1 Frequent ACA of CML in different disease phases

Abnormal pattern Phase

Newly diagnosed CP(n01,239), N (%)

CP after therapy(n0814), N (%)

AP (n096), N (%) BC (n0223), N (%)

Total ACA ratio 39 (3.1) 74 (9.1) 34 (35.4) 118 (52.9)

Numerical abnormalities 21 (1.7) 34 (4.2) 20 (20.8) 84 (37.7)

Hyperdiploid 4 (0.3) 22 (2.7) 15 (15.6) 52 (23.3)

Hypodiploid 17 (1.4) 10 (1.2) 5 (5.2) 27 (12.1)

Pseudodiploidy 0 (0) 2 (0.3) 0 (0) 5 (2.2)

Additional copies of Ph 2 (0.2) 10 (1.2) 10 (10.4) 35 (15.7)

Trisomy 8 1 (0.1) 10 (1.2) 9 (9.4) 26 (11.7)a

Trisomy 21 0 2 (0.3) 3 (3.1) 11 (4.9)

Trisomy 19 0 4 (0.5) 5 (5.2) 10 (4.5)

Monosomy 7 0 1 (0.1) 1 (1.0) 9 (4.0)

Loss of Y 8 (1.0) 2 (0.4) 1 (1.6) 4 (2.5)

Structural abnormalities 19 (1.5) 47 (5.8) 22 (22.9) 76 (34.1)

Abnormality of 1p 1 (0.1) 2 (0.3) 1 (1.0) 4 (1.8)

Abnormality of 1q 0 (0) 4 (0.5) 1 (1.0) 6 (2.7)

Abnormality of 3q 1 (0.1) 5 (0.6) 3 (3.1) 8 (3.6)

Abnormality of 7p 1 (0.1) 0 0 5 (2.2)

Abnormality of 7q 1 (0.1) 7 (0.9) 0 8 (3.6)

Abnormality of 9p 0 0 1 (1.0) 7 (3.1)

Loss of 17pb 3 (0.2) 10 (1.2) 8 (8.3) 22 (9.9)

a Including three cases with tetrasomy 8b Including deletion of 17p and isochromosome of 17q

Table 2 Comparison of ACAbetween standard t(9;22) andvariant Ph translocations

NS not significant

Phase ACA in standard t(9;22), N (%) ACA in variant t(9;22), N (%) P value

Newly diagnosed CP 35/1,180 (3.0) 4/59 (6.8) NS

CP after therapy 64/762 (8.4) 10/52 (19.2) 0.017

AP 31/89 (34.8) 3/7 (42.9) NS

BC 103/206 (50.0) 15/17 (88.2) 0.002

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abnormalities more frequently seen in myeloid-BC patients.As shown in Table 4, myeloid-BC with minimal differentia-tion had more ACA (including hyperdiploid karyotype), ad-ditional copies of the Ph chromosome, trisomy 8, and variant t(9;22) when compared to myeloid-BC with granulocytic dif-ferentiation (80% vs. 46.8%, P00.009) or monocytic differ-entiation (80% vs. 42.9%, P00.006). Moreover, significantdifferences were also observed in hyperdiploid karyotype andadditional copies of the Ph chromosome (excluding myeloidwith minimal differentiation vs. myeloid with granulocyticdifferentiation). Although myeloid with erythroid differentia-tion harbored more hyperdiploid karyotypes than other mye-loid phenotypes, statistical analysis was not conducted due toa low number of cases.

Discussion

Since the Ph chromosome was first reported in 1960 and itsmechanism was revealed in 1973 [12, 13], a large number ofcytogenetic studies have been reported to shed light on thenature of CML. Cytogenetic analyses of CML have beenperformed previously in a large number of reports, but fewstudies focused on the geographic heterogeneity of cytogenet-ic abnormalities and the association between ACA and variantPh translocations in CML. Our study containing cytogeneticdata of 1,863 CML cases, the largest series of CML patients inChina to our knowledge, further elucidated the cytogeneticnature of CML.

Our survey of 1,266 newly diagnosed patients showedthat CML occurred in all ages, but predominantly in 30 to49 years. The median age was 41 years for males and42 years for females. This is much younger than that ofwestern populations (65 years in UK [14], 68 years in USA[14], 60.3 years in Germany [15], and 55 years in France[16]) and was similar to that of Asian populations (36 to38 years in Thailand, 43 years in Singapore, 37 years inSouth Korea, and 38 to 40 years in India [17]). Environ-mental pollution can increase the risk of leukemia [18, 19],while residents of Asia may have higher exposures to airpollution than those in Western industrial nations becausethey spend more time outdoors and their living environ-ments are more deleterious [20]. Therefore, we speculatedthis age discrepancy of CML afflicted might be associatedwith environmental pollution. Besides, regional and ethnicdifferences could be another possible explanation.

ACA, being a common phenomenon in CML, tend toincrease as the disease progresses. In these cohort cases, therate of ACA grew gradually from newly diagnosed CP toBC. Although the ACA rate in newly diagnosed CP, CPafter therapy, and AP were seldom reported, the rate in BCwas only 52.9% in our series, which was lower than 60–80% in previous studies [6, 21–25]. This discrepancy might

be attributed to various factors: (1) there were differentdiagnostic criteria for BC. BC required more than 30%blasts in the patient's bone marrow or peripheral bloodbefore 2001 and more than 20% blasts after 2001. Weadopted the latter. (2) The treatment of tyrosine kinaseinhibitors might decrease the ACA rate in CML-BC. In thisstudy, 31 patients received imatinib or other novel tyrosinekinase inhibitors before BC, and the ACA rate was 42.4%,lower than 54.8% in patients without tyrosine kinase inhib-itors therapy before BC. (3) Different laboratories use band-ing techniques which may bring about discrepant results.

As previous papers described [4, 21, 26], trisomy 8, addi-tional copies of Ph, and i(17q) were the most frequent ACA,while trisomy 19 and trisomy 21 were also common chromo-some abnormalities in these patients. It is well known thatDown syndrome is characterized by trisomy 21. However, inour 15 cases with trisomy 21 (one was presented in AP andBC), the chromosomal abnormality did not occur at diagnosisor disappeared in the process of therapy. Hence, these patientscould be excluded from Down syndrome. Moreover, five of15 cases with loss of Y cannot be identified as disease relateddue to lack of analysis of constitutional or sequential karyo-types. So, the loss of Y rate was possibly overestimated in thisstudy because loss of Y is frequently observed in healthyelderly men.

Although a strong association between ACA and trans-formation of CML has been undoubtedly proven, the impactof these secondary abnormalities on prognosis seems to becomplex. Most studies showed that ACA during BC con-ferred a worse prognosis [27]. However, Majlis et al. [28]reported that before BC, chromosome 17 abnormality had aworse outcome, while chromosome 8 abnormality seemedto convey different prognosis in patients with greater than orless than 40% abnormal metaphases. In the imatinib era,ACA developing during the course of CML patients' thera-py was considered a feature of acceleration and conveyed apoor prognosis [29, 30]. Of these secondary abnormalities,major-route ACA, such as loss of 17p, trisomy 8, additionalcopies of Ph, and trisomy 19, and complex abnormalitieshad the worst outcome [31]. A recent report showed thatthere were no difference on prognosis between minor-routeACA at diagnosis, such as t(3;12), t(4;6), t(1;21), and -Y,and standard t(9;22) without no ACA, but major-route ACAat diagnosis had also a poor outcome, suggesting that thesepatients should be closely monitored and need early andintensive intervention such as early SCT [32].

Variant Ph translocations, involving one or more chro-mosomal regions in addition to 9 and 22, were reported in5–10% of CML [33, 34], most of which occur in CP,especially at the time of diagnosis [27]. In the pre-imatinibera, some reports have revealed that there was a strongassociation between variant Ph translocations and deletionsin derivative chromosome 9, implying that they may have a

Ann Hematol (2012) 91:1065–1072 1069

worse outcome than standard t(9;22) [35, 36]. In the imati-nib era, however, the presence of variant Ph translocationshas no impact on prognosis [37]. In our study, the ACArates of variant Ph translocations in newly diagnosed CP,CP after therapy, AP, and BC all were higher than thoseof standard t(9;22). Significant differences were observedin CP after therapy and BC but not in newly diagnosedCP and AP. One possible reason may be that the ACArate in newly diagnosed CP is low because this is anearlier stage of CML. Also, sample size was small in APin this cohort. Among patients with variant Ph trans-locations, 24 (one of them had ACA in AP and BC)were treated with HU, IFN, or chemotherapy, and threereceived short-term imatinib therapy prior to occurrenceof ACA which disappeared immediately. Hence, the closerelation between ACA and variant Ph translocations wassuitable to the pre-imatinib era.

Like previous observations [5, 8, 9], trisomy 8, loss of17p, trisomy 19, and trisomy 21 were more frequently seenin myeloid-BC patients than in lymphoid-BC patients in ourstudy, but a significant difference was only observed for

trisomy 8. Interestingly, hyperdiploid karyotypes occurredmore frequently in myeloid-BC than in lymphoid-BC, whilethe opposite occurred in the hypodiploid karyotype (both P<0.05). In a previous study, abnormalities of chromosome 7were correlated with lymphoid-BC [38], which were asso-ciated with deletions of immunoglobulin heavy chain and Tcell receptor gene regions [39].

Investigations on the correlation between chromosomalabnormalities and myeloid-BC or lymphoid-BC werereported previously in the literature. However, to our knowl-edge, the association of chromosomal abnormalities, espe-cially ACA, with subsets of myeloid-BC has not beendescribed. Hence, we studied frequent cytogenetic abnor-malities in subsets of myeloid-BC patients. In our cohort,compared with myeloid with granulocytic differentiation ormonocytic differentiation, myeloid with minimal differenti-ation had distinct features, including the higher rate of ACA,hyperdiploid karyotype, and additional copies of the Phchromosome. It is very similar to the incidence of aberrantkaryotype in myeloid leukemia with minimal differentiation(FAB M0) in acute myeloid leukemia (AML), which is

Table 3 Frequent chromosomalaberrations in relation to sub-types of CML-BC

NS not significant

Chromosomal abnormalities Lymphoid-BC(n058), N (%)

Myeloid-BC(n0140), N (%)

P value

ACA 31 (53.4) 73 (52.1) NS

Hyperdiploid karyotype 8 (13.8) 38 (27.1) 0.043

Hypodiploid karyotype 12 (20.7) 11 (7.9) 0.01

Additional copies of Ph 7 (12.1) 23 (16.4) NS

Trisomy 8 2 (3.4) 21 (15.0) 0.021

Loss of 17p 2 (3.4) 15 (10.7) NS

Monosomy 7 7 (12.1) 2 (1.4) 0.004

Abnormality of 7q 0 7 (5.0) NS

Trisomy 19 1 (1.7) 8 (5.7) NS

Trisomy 21 0 9 (6.4) NS

Variant t(9;22) 1 (1.7) 14 (9.3) 0.088

Table 4 Comparison of frequent chromosome abnormalities among subsets of myeloid-BC

Chromosomalabnormalities

Minimaldifferentiation(n020), N (%)

Granulocyticdifferentiation(n062), N (%)

Monocyticdifferentiation(n042), N (%)

Granulo-monocyticdifferentiationa

(n09), N (%)

Erythroiddifferentiationa

(n06), N (%)

ACA 16 (80.0) 29 (46.8)** 18 (42.9)** 7 (77.8) 4 (66.7)

Hyperdiploid karyotype 10 (50.0) 16 (25.8)* 5 (11.9)** 2 (22.2) 4 (66.6)

Additional copies of Ph 6 (30.0) 11 (17.7) 3 (7.1)* 1 (11.1) 1 (16.7)

Trisomy 8 6 (30.0) 7 (11.3) 4 (9.5) 2 (22.2) 2 (33.3)

Loss of 17p 2 (10.0) 7 (11.3) 5 (11.9) 1 (11.1) 0

Variant t(9;22) 4 (20.0) 6 (9.7) 3 (7.1) 1 (11.1) 1 (16.7)

Excluding one myeloid-BC case with megakaryocytic differentiation

*P<0.05; **P<0.01 (compared with minimal differentiation)a Statistical analysis not performed due to the small number of cases

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much higher than that in other FAB subtypes (excluding M3and M7) [40, 41].

A limitation of this study is that the impacts of thesesecondary abnormalities on prognosis could not be evalu-ated due to lack of regular cytogenetic and molecularmonitoring, especially in the pre-imatinib era. However,we analyzed cytogenetic characteristics of 1,863 CMLpatients from the Chinese population and compared thecorrelation between subtypes of CML-BC and cytogeneticabnormalities and the association between ACA and var-iant Ph translocations. Our findings will contribute deeplyto understanding the nature of CML.

Acknowledgements The authors would like to thank Mr. CollesPrice from the University of Chicago Medical Center, Chicago, IL,USA, for grammatical and cosmetic polishing in English writing.

Author's contributions Qitian Mu designed the research, collectedand analyzed data, and wrote the manuscript. Qiuling Ma collected andanalyzed data. Yungui Wang, Zhimei Chen, Xiangmin Tong, Fei-FeiChen, and Ying Lu collected data and performed research. Jie Jindesigned the research and reviewed the manuscript.

Conflicts of interest The authors declare no conflicts of interest.

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