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J Cancer Metastasis Treat 2017;3:38-44.10.20517/2394-4722.2016.61© 2017 OAE Publishing Inc.
Open AccessReview

Cytogenetic and molecular basis of BCR-ABL myelodysplastic syndrome: diagnosis and prognostic approach

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Health Research Institute, Thalassemia and Hemoglobinopathy Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 61357-15794, Iran.

Correspondence Address: Dr. Najmaldin Saki, Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 61357-15794, Iran. E-mail: najmaldinsaki@gmail.com

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    Abstract

    Myelodysplastic syndromes (MDS) include a heterogeneous group of blood disorders generally afflicting older people. Several genetic factors have been reported from these patients that have an important role in the diagnosis, prognosis, and treatment of this disease. BCR-ABL1 is a genetic factor that has occasionally been reported in some studies. This review attempts to characterize MDS patients reported to harbor this fusion and to assess the diagnostic, therapeutic, and prognostic potential of BCR-ABL1 fusionin MDS patients. This review showed that BCR-ABL fusion has been reported in 22 MDS patients whose condition generally transformed to acute myeloblastic leukemia and was not responsive to conventional therapies. However, these patients showed a good response to treatment with tyrosine kinase inhibitors. Therefore, even though incidence of BCR-ABL fusion appears to be low in MDS patients, its detection is essential in assessing disease prognosis and choosing appropriate treatment.

    Introduction

    Myelodysplastic syndromes (MDS) are a group of clonal myeloid disorders with morphological characteristics such as hypercellular bone marrow (BM), single- or multilineage dysplasia, and cytopenia in peripheral blood (PB).[1,2] Mortality associated with cytopenia and risk of transformation to acute myeloblastic leukemia (AML) are important problems for MDS patients. In fact, one-third of MDS patients become AML patients, and the remaining two-thirds succumb to progressive BM failure, which leads to bleeding, frequent infections, and severe anemia.[3] MDS is generally an adult disease with an average age upon diagnosis of 65-70 years; less than 10% of patients are younger than 50 years. The annual incidence rate of MDS is approximately 5 cases per 100,000 population; incidence increases to 22-45 cases per 100,000 in people over 70 years of age.[4] MDS is generally diagnosed by accurate assessment of PB followed by morphological BM examination. According to the 2016 WHO revision, MDS patients are divided into lower- and higher-risk MDS. Lower-risk MDS conditions that have below 5% of blasts include: MDS with single-lineage dysplasia, MDS with single-lineage dysplasia and ring sideroblasts (RS), MDS with multilineage dysplasia without RS and with RS, MDS with isolated del (5q), and MDS unclassifiable (MDS-U). Higher-risk MDS conditions (5-19 blasts) include: MDS-EB1 (5-9% blast and/or 2-4% in PBS) and MDS-EB2 (10-19% blasts; Auer rods, or 5-19% in PBS).[5]

    t(9;22) (q34;q11.2) translocation and its variants give rise to Philadelphia chromosome (Ph), which results in juxtaposition of DNA sequence of BCR and ABL1 genes, mRNA translation of this chimeric gene, and eventual dysregulated expression of oncogenic tyrosine kinase of BCR-ABL1 fusion, which seems to be sufficient to initiate the leukemogenesis process.[6] Three different forms of BCR-ABL1 fusion protein are produced based on the breakpoint site in the BCR gene: p190, p210, and p230. Although they are all associated with development of leukemia, these three forms have different clinical outcomes.[7] Although BCR-ABL1 chromosomal abnormality is pathognomic for chronic myeloid leukemia (CML), it is observed de novo in B-cell precursor acute lymphoblastic leukemia (ALL), especially in adults, as well as in 0.48-3% of patients with AML.[8,9] In contrast, Ph is extremely rare in MDS patients and shows up in the last stages of disease, so it is associated with leukemic transformation in most cases.[10] Although few cases of Ph+ MDS have been reported, diagnosis of this disorder is especially important, since these patients show a poor response to conventional therapeutic approaches.[11]

    The presence of common traits in MDS and myeloproliferative disease (MPD) suggests that some genetic abnormalities associated with MPD are most likely involved in the development or progression of MDS. Lack of knowledge about the importance of this abnormality in MDS patients may lead to inaccurate assessment of BCR-ABL fusion and choice of an inappropriate therapeutic protocol. Therefore, besides studying the reported cases, this review aims to investigate the typical features of Ph+ MDS patients and will assess the role of genetic abnormalities, especially the impact of BCR-ABL fusion, on response to treatment in MDS patients.

    Cytogenetic and molecular markers

    All classification and prognosis systems of MDS in recent decades have been based on cytomorphological findings in PB and BM, including May-Grünwald-Giemsa (MGG) staining, myeloperoxidase staining, nonspecific esterases (especially for CMML), as well as iron staining and assessment of cytopenia.[12] MDS diagnosis is often challenging for several reasons, such as varying clinical manifestations in different patients and the absence of dysplasia in some cases. For this reason, cytogenetic tests have been introduced for correct diagnosis of some MDS subtypes; for example, in the fourth classification of WHO, del 5q is considered as a separate subgroup. In patients whose diagnosis is controversial, cytogenetic analysis seems to be a helpful addition to clinical and hematological findings when seeking a definitive diagnosis.[13]

    Genetic abnormalities in MDS patients include deletions, gains, and chromosomal rearrangements, as well as molecular changes such as point mutations, epigenetic changes, and dysregulated miRNAs.[13] Conventional cytogenetics and fluorescent in situ hybridization (FISH) analysis are commonly used methods for detection of karyotype abnormalities; both methods have advantages and disadvantages. Karyotype commonly evaluates 20 metaphase cells. FISH analysis can detect chromosomal abnormalities with a higher resolution, but it is limited to regions with predefined probes.[14] Therefore, it seems prudent to perform initial assessment by conventional karyotyping and to use FISH analysis for further investigations. Several studies have shown that FISH analysis in conjunction with karyotyping can provide further information, especially in cases where the karyotype appearsnormal.[15,16] Chromosomal abnormalities have been detected in approximately 50% of patients with de novo MDS and in more than 80% of MDS cases secondary to chemotherapy and toxic agents. In a large-scale study on 2124 MDS patients, 48% had normal karyotype and 52% showed abnormal karyotype. The most common cytogenetic abnormality was del 5q in 30% of patients, followed by -7/del 7q in 21%, and +8 in 16% of cases.[17] Detection of cytogenetic abnormalities plays a significant role in disease prognosis, so it has been recognized as a marker in all the prognostic systems, including international prognostic scoring system (IPSS), revised-international prognostic scoring system (IPSS-R), and WPSS. IPSS-R isone of the most widely used prognostic systems for MDS patients.[18] In this classification system, -Y and del (11q) have a very good prognosis; normal karyotype, del (5q), del (12p), del (20q), and double including del (5q) have good prognosis; del (7q), +8, +19, and i (17q) a moderate prognosis; -7, inv (3)/t (3q), double including -7/del (7q), complex 3 abnormalities have poor prognosis; and finally patients with karyotype of complex with > 3 abnormalities have a very poor prognosis.[19]

    Technological advances in the field of genetic analysis, including high-through put next-generation sequencing (HT-NGS), led to the discovery of several genetic mutations in MDS patients.[20] Studies have shown that approximately 83% of MDS patients show genetic mutations.[21] In Table 1, some of the most common mutant genes in MDS patients are summarized.

    Table 1

    The most common mutations in myelodysplastic syndromes

    Mutated genePrevalence (%)PrognosisRef.
    RNA splicingSF3B116Favorable[22,23]
    SRSF213Poor
    U2AF110Poor
    DNA methylationTET223Favorable[24]
    DNMT3A9Poor[25]
    IDH1/27.5Poor[26]
    Chromatin modificationASXL120Poor[27]
    EZH26Poor[28]
    OncogenesTp539.4Poor[29]
    Ras15Poor[30]
    EVI11-2Poor[31]
    OthersRUNX112Poor[32]
    JAK253 in RARS-TNot studied[33]

    Although these mutations involve a range of genes, their use as a diagnostic marker for MDS patients is difficult. A good diagnostic marker must have a high incidence in patients as well as an acceptable level of specificity, but none of these genes has a high prevalence in MDS patients (low frequency), and no mutant gene has been specifically reported for MDS.[34] Mutations have been partially assessed as prognostic markers and have generally been associated with poor prognosis.[14] Therefore, although these mutations seem to be good prognostic factors, prognostic systems have not yet taken advantage of them in their classifications.[18]

    Diagnosis and prognosis

    According to search of MEDLINE database, there have been 22 cases of MDS patients harboring BCR-ABL1 chromosome abnormality. There were 15 male and 7 female patients that were classified into two groups: adults with an average age of 64.5 years and children with an average age of 25 months. Mean hemoglobin concentration was 8.4 g/dL (94.7% had hemoglobin levels less than 11.5 g/dL, i.e. were anemic). Mean white blood cell count was 6.7 × 106/mL and mean platelet count was 135 × 103/mL (61.1% had platelet counts lower than 100 × 103). Karyotype analysis in 20 cases revealed t (9:22) translocation, but in two other cases, FISH test indicated the presence of Phfusion despite normal karyotype.[11,35] Molecular analysis was done in only 10 cases; of these 5 represented Ph P190 variant, 4 cases had Ph210, and 1 case had both variants [Table 2]. According to these findings, Ph fusion was most prevalent in RAEB subgroup; 54.6% of cases (including 27.3% RAEB, 9.1% RAEB2, and 18.2% of RAEBt) were classified in this subgroup, followed by RA in 13.6% of cases. This finding was in contrast to some extensive studies of the epidemiology of different subtypes of MDS, which indicate that RA, RARS, RAEB, and RAEBt are the most common subtypes, respectively.[17,36] There was a relatively poor prognosis in these patients. Only 5 patients responded to treatment, among which 2 cases were treated with imatinib.[11,13] Forty-five percent (n = 10) of patients progressed to AML, among whom 3 patients showed P190 variant, 3 patients showed P210, and 1 patient showed both variants[Table 2]. Only one patient showing P190 variant progressed to ALL. Three patients progressed to CML for whom unfortunately no molecular study was conducted.[4,9,13]

    Table 2

    Characteristics of MDS patients with BCR-ABL fusion

    No. Age/gender MDS subtype Ph+ phase/type Cytogenetic findings Hematological findings Outcome Ref.
    1 69/M RAEBt At diagnosis/P190 46, XY[3]/45, X, -y[2]/50, XY, +Y, -3, del5 (q12q34), +8, +14, add(18)(p11), +22, +min[11]/idem, t(9;22) (q34;q11) Hb = 8.1 Progressed to AML/died [37]
    WBC = 5.3
    Plt = 77
    2 64/M RAEB At diagnosis/P190 46, XY[7]/47, XY, +8, t(9;22) (q34;q11)[6] Hb = 7.8 Progressed to AML/died [37]
    WBC = 6.9
    Plt = 98
    3 3/M RAEBt AML late stage transformation/P210 46, XY, t(9;22)(q34;q11) Hb = 6.2 Progressed to AML [38]
    WBC = 4.7
    Hb = 47
    4 54/M RA ALL transformation stage/P190 46, XY, t (9;22) (q34;q11).20q- (18/20)/46, XY, 20q- Hb = 8.6 Progressed to ALL/died [39]
    WBC = 3.2
    Plt = 142
    5 78/M RAEBt At diagnosis/P190 46, XY, der (3) t(1;3) (p22;p14), del (5) (q13q33)/ FISH revealed fusion signal of BCR and ABL probes on an apparently normal chromosome 22 Hb = 9.8 Died in 5 months [35]
    WBC = 13.5
    Plt = 29
    6 67/F RAEB-2 At diagnosis/ P210(b2a2) Ph+ [29/30], normal [1/30] Hb = 11.5 Complete remission with imatinibmesylate [11]
    WBC = 3.4
    Plt = 111
    7 39/M RAEB AML transformation/ early stage p210 and late stage p210 and p190 46, XY, t (3;3)(y21:q26)[50] 46, XY, del (l)(p22). t(3;3) (q21: y26). -16[6]
    46, XY, t(3;3)(q21:q26), t (9;22) (q34:q11)[3]
    Hb = 7.1 Progressed to AML/died [40]
    WBC = 7.1
    Plt = 547
    8 25 months/F unclassified At diagnosis/- 46, XX, t (9;22) (q34;q11) [15] Hb = 8.7 Died in 28 months [10]
    WBC = 7.9
    Plt = 39
    9 20 months/F unclassified 24 months after diagnosis/- 37-45, XX, −18[7]/46, XX[4]. nuc fish 9q34 (abl×2), 22q11 (bcr×2) (ablcon bcr×1) [4/200] Hb = 5.9 Treated with low dose chemotherapy [10]
    WBC = 26.3
    Plt = 71
    10 73/M CMMoL 7 months after diagnosis/- 46, XY, t(4;6) (p15;p12), t(9;22) (q34;q11) [10%] Hb = 15.4 CML/died in 10 months [41]
    WBC = 18.1
    Plt = 31
    11 63/M RA During myeloproliferative phase/- 46, XY, t(9;22) (q34;q11) [100%] Hb = 10.2 CML/died in 3 months [41]
    WBC = 1.4
    Plt = 165
    12 66/M RAEB-2 AML transformation/ P190 Karyotype was neg for Ph but FISH indicate a fusion signal in 60% Hb = 6.2 Progressed to AML/died [42]
    WBC = 1.7
    Plt = 33
    13 73/M RAEB In CML transformation/P210 46, XY, t (9;22)/fish indicated single Ph 98.0% - Progressed to CML then all died [43]
    14 66/F RAEB At diagnosis/- 47, XX, +8, t(9;22;16) (q34;q11.2;q23) [4]/46, XX, idem, der (12) t(12;17) (p11.2;q11.2) [7]/46, XX[9] Hb = 4.4 Progressed to granulocytic sarcoma skin in 9 months and died 1 month later [44]
    WBC = 0.9
    Plt = 52
    15 71/M RAEB At diagnosis/- 46, XY, t(9;22) (q34;q11) [20] Hb = 9 Progressed to RAEBt in 5 months and died 9 months after diagnosis [44]
    WBC = 4000
    Plt = 55
    16 59/M RAEB At diagnosis/P210 46, XY, t(9;22) (q34;q11) [20] Hb = 9.2 Progressed to AML/treated with allogeneic transplant [44]
    WBC = 1.3
    Plt = 78
    17 78/F RCMD At CML transformation/- 46, XX, t(9;22) (q34;q11) Hb = 10.2 Progressed to CML accelerated phase/response to imatinib with significant cytopenia [45]
    WBC = 2.6
    Plt = 152
    18 56/M RA At diagnosis/- Complex karyotype with PH1 chromosome Hb = 4.8 Progressed to AML/died [46]
    WBC = 2.4
    Plt = 350
    19 49/F - At diagnosis/- t(9;22) (q34;q11) [38%] Hb = 8.2 Progressed to AML/died [47]
    WBC = 6.5
    Plt = 425
    20 62/M RAEB AML transformation t(9;22) (q34:q11) [100%] Hb = 9.8 Progressed to AML/died [48]
    WBC = 3.2
    Plt =120
    21 70/F RARS At diagnosis/- 46, XX[3]/46, XX, t(9q;22q) [12] Hb = 9.5 Stable/alive [49]
    WBC = 6.4
    Plt = 316
    22 69/M t-MDS AML transfomation 46, XY, t(9;22)(q34;q11) [35] Hb (no data)Progressed to AML [50]
    WBC = 1.3
    Plt = 129

    Discussion and future prospective

    Using current advances in molecular diagnosis, several genetic factors have been identified in MDS patients with occasional diagnostic, prognostic, and therapeutic value. Ph chromosome is a factor intermittently reported in some cases of MDS. Given the pathognomic role of Ph in other hematologic neoplasms, it is assumed that in case of high incidence of Ph in MDS patients, an MDS subgroup known as Ph+ MDS can be introduced. However, the importance of this genetic abnormality in MDS patients has not been extensively studied in MDS patients up to the present time.

    The fact that only 22 cases of Ph+ MDS have been reported to date is not conclusive evidence of low prevalence of this fusion in MDS patients. We state this for two reasons: (1) retrospective studies are inefficient for these patients because of the lack of careful examination of BCR-ABL fusion, and (2) no study up to the present time has specifically examined this fusion in MDS patients. Given that in some cases only FISH analysis has managed to detect BCR-ABL fusion in MDS patients, lack of detection in normal karyotype analysis does not indicate definitive absence of this fusion.[5,11] Assessment of reported cases shows that MDS patients harboring this chromosomal abnormality typically do not respond well to conventional treatments but do show a good response to imatinib therapy.[11,13] Since imatinib is not routinely used in treatment of MDS patients, lack of Ph detection in these patients may lead to incorrect treatment and thus put the patient’s life at risk.

    In general, although the findings of this study indicate the importance of Ph detection in MDS patients, they are not sufficient to clarify the precise role of Ph in MDS patients. Therefore, specific assessment of this chromosomal abnormality in MDS patients is recommended in future studies.

    Authors’ contributions

    Manuscript’s conception and revision: N. Saki, M. Paridar

    Writing the manuscript: O.K. Ghalesardi, M. Seghatoleslami, A. Ahmadzadeh

    Tables’ preparation: A. Khosravi

    Acknowledgments

    This paper forms part of M.Sc. thesis belonging to Omid Kiani Ghalesardi.

    Financial support and sponsorship

    This work was financially supported by grant TH94/11 from Vice-chancellor for Research Affairs of Ahvaz Jundishapur University of Medical Sciences.

    Conflicts of interest

    There are no conflicts of interest.

    Patient consent

    Patient consent was obtained.

    Ethical approval

    This article does not contain any studies involving human or animal subjects.

    References

    • 1. Cogle CR, Saki N, Khodadi E, Li J, Shahjahani M, Azizidoost S. Bone marrow niche in the myelodysplastic syndromes. Leuk Res 2015;39:1020-7.

      DOIPubMed
    • 2. Visconte V, Selleri C, Maciejewski JP, Tiu RV. Molecular pathogenesis of myelodysplastic syndromes. Transl Med Uni Sa 2014;8:19-30.

    • 3. Shukron O, Vainstein V, Kündgen A, Germing U, Agur Z. Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database. Am J Hematol 2012;87:853-60.

      DOIPubMed
    • 4. Greenberg PL, Attar E, Bennett JM, Bloomfield CD, Borate U, De Castro CM, Deeg HJ, Frankfurt O, Gaensler K, Garcia-Manero G, Gore SD, Head D, Komrokji R, Maness LJ, Millenson M, O'Donnell MR, Shami PJ, Stein BL, Stone RM, Thompson JE, Westervelt P, Wheeler B, Shead DA, Naganuma M. Myelodysplastic syndromes: clinical practice guidelines in oncology. J Natl Compr Canc Netw 2013;11:838-74.

      DOIPubMedPMC
    • 5. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009;114:937-51.

      DOIPubMed
    • 6. Rana A, Ali GM, Ali S, Khan A, Mansoor S, Malik S, Farooqi AA. BCR-ABL1 in leukemia: disguise master outplays riding shotgun. J Cancer Res Ther 2013;9:6-10.

      DOIPubMed
    • 7. Tala I, Chen R, Hu T, Fitzpatrick ER, Williams DA, Whitehead IP. Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression. Leukemia 2013;27:1080-9.

      DOIPubMedPMC
    • 8. Nacheva EP, Grace CD, Brazma D, Gancheva K, Howard-Reeves J, Rai L, Gale RE, Linch DC, Hills RK, Russell N, Burnett AK, Kottaridis PD. Does BCR/ABL1 positive acute myeloid leukaemia exist? Br J Haematol 2013;161:541-50.

    • 9. Neuendorff NR, Schwarz M, Hemmati P, Türkmen S, Bommer C, Burmeister T, Dörken B, le Coutre P, Arnold R, Westermann J. BCR-ABL1(+) acute myeloid leukemia: clonal selection of a BCR-ABL1(-) subclone as a cause of refractory disease with nilotinib treatment. Acta haematol 2015;133:237-41.

      DOIPubMed
    • 10. Dalla Torre CA, de Martino Lee ML, Yoshimoto M, Lopes LF, Melo LN, Caminada de Toledo SR, Duffles Andrade JA. Myelodysplastic syndrome in childhood: report of two cases with deletion of chromosome 4 and the Philadelphia chromosome. Leuk Res 2002;26:533-8.

      DOI
    • 11. Drummond MW, Lush CJ, Vickers MA, Reid FM, Kaeda J, Holyoake TL. Imatinib mesylate-induced molecular remission of Philadelphia chromosome-positive myelodysplastic syndrome. Leukemia 2003;17:463-5.

      DOIPubMed
    • 12. Haferlach T. Molecular genetics in myelodysplastic syndromes. Leuk Res 2012;36:1459-62.

      DOIPubMed
    • 13. Nybakken GE, Bagg A. The genetic basis and expanding role of molecular analysis in the diagnosis, prognosis, and therapeutic design for myelodysplastic syndromes. J Mol Diagn 2014;16:145-58.

      DOIPubMed
    • 14. Lee EJ, Podoltsev N, Gore SD, Zeidan AM. The evolving field of prognostication and risk stratification in MDS: recent developments and future directions. Blood rev 2016;30:1-10.

      DOIPubMed
    • 15. Jiang H, Xue Y, Wang Q, Pan J, Wu Y, Zhang J, Bai S, Wang Q, He G, Sun A, Wu D, Chen S. The utility of fluorescence in situ hybridization analysis in diagnosing myelodysplastic syndromes is limited to cases with karyotype failure. Leuk Res 2012;36:448-52.

      DOIPubMed
    • 16. Yang W, Stotler B, Sevilla DW, Emmons FN, Murty VV, Alobeid B, Bhagat G. FISH analysis in addition to G-band karyotyping: utility in evaluation of myelodysplastic syndromes? Leuk Res 2010;34:420-5.

    • 17. Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger T, Hildebrandt B, Kundgen A, Lübbert M, Kunzmann R, Giagounidis AA, Aul C, Trümper L, Krieger O, Stauder R, Müller TH, Wimazal F, Valent P, Fonatsch C, Steidl C. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 2007;110:4385-95.

      DOIPubMed
    • 18. Bejar R, Steensma DP. Recent developments in myelodysplastic syndromes. Blood 2014;124:2793-803.

      DOIPubMed
    • 19. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstöcker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012;120:2454-65.

      DOIPubMedPMC
    • 20. Visconte V, Tiu RV, Rogers HJ. Pathogenesis of myelodysplastic syndromes: an overview of molecular and non-molecular aspects of the disease. Blood Res 2014;49:216-27.

      DOIPubMedPMC
    • 21. Walter MJ, Shen D, Shao J, Ding L, White BS, Kandoth C, Miller CA, Niu B, McLellan MD, Dees ND, Fulton R, Elliot K, Heath S, Grillot M, Westervelt P, Link DC, DiPersio JF, Mardis E, Ley TJ, Wilson RK, Graubert TA. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia 2013;27:1275-82.

      DOIPubMedPMC
    • 22. Kang MG, Kim HR, Seo BY, Lee JH, Choi SY, Kim SH, Shin JH, Suh SP, Ahn JS, Shin MG. The prognostic impact of mutations in spliceosomal genes for myelodysplastic syndrome patients without ring sideroblasts. BMC Cancer 2015;15:484.

      DOIPubMedPMC
    • 23. Mian SA, Smith AE, Kulasekararaj AG, Kizilors A, Mohamedali AM, Lea NC, Mitsopoulos K, Ford K, Nasser E, Seidl T, Mufti GJ. Spliceosome mutations exhibit specific associations with epigenetic modifiers and proto-oncogenes mutated in myelodysplastic syndrome. Haematologica 2013;98:1058-66.

      DOIPubMedPMC
    • 24. Kosmider O, Gelsi-Boyer V, Cheok M, Grabar S, Della-Valle V, Picard F, Viguié F, Quesnel B, Beyne-Rauzy O, Solary E, Vey N, Hunault-Berger M, Fenaux P, Mansat-De Mas V, Delabesse E, Guardiola P, Lacombe C, Vainchenker W, Preudhomme C, Dreyfus F, Bernard OA, Birnbaum D, Fontenay M; Groupe Francophone des Myélodysplasies. TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs). Blood 2009;114:3285-91.

      DOIPubMed
    • 25. Lin J, Yao DM, Qian J, Chen Q, Qian W, Li Y, Yang J, Wang CZ, Chai HY, Qian Z, Xiao GF, Xu WR. Recurrent DNMT3A R882 mutations in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome. PLoS One 2011;6:e26906.

    • 26. Jin J, Hu C, Yu M, Chen F, Ye L, Yin X, Zhuang Z, Tong H. Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis. PloS One 2014;9:e100206.

    • 27. Thol F, Friesen I, Damm F, Yun H, Weissinger EM, Krauter J, Wagner K, Chaturvedi A, Sharma A, Wichmann M, Göhring G, Schumann C, Bug G, Ottmann O, Hofmann WK, Schlegelberger B, Heuser M, Ganser A. Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes. J Clin Oncol 2011;29:2499-506.

      DOIPubMed
    • 28. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tönnissen ER, van der Heijden A, Scheele TN, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 2010;42:665-7.

      DOIPubMed
    • 29. Kulasekararaj AG, Smith AE, Mian SA, Mohamedali AM, Krishnamurthy P, Lea NC, Gäken J, Pennaneach C, Ireland R, Czepulkowski B, Pomplun S, Marsh JC, Mufti GJ. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. Br J Haematol 2013;160:660-72.

      DOIPubMed
    • 30. Constantinidou M, Chalevelakis G, Economopoulos T, Koffa M, Liloglou T, Anastassiou C, Yalouris A, Spandidos DA, Raptis S. Codon 12 ras mutations in patients with myelodysplastic syndrome: incidence and prognostic value. Ann Hematol 1997;74:11-4.

      DOIPubMed
    • 31. Haferlach C, Bacher U, Haferlach T, Dicker F, Alpermann T, Kern W, Schnittger S. The inv (3)(q21q26)/t(3;3)(q21;q26) is frequently accompanied by alterations of the RUNX1, KRAS and NRAS and NF1 genes and mediates adverse prognosis both in MDS and in AML: a study in 39 cases of MDS or AML. Leukemia 2011;25:874-7.

      DOIPubMed
    • 32. Chen CY, Lin LI, Tang JL, Ko BS, Tsay W, Chou WC, Yao M, Wu SJ, Tseng MH, Tien HF. RUNX1 gene mutation in primary myelodysplastic syndrome -- the mutation can be detected early at diagnosis or acquired during disease progression and is associated with poor outcome. Br J Haematol 2007;139:405-14.

      DOIPubMed
    • 33. Hellström-Lindberg E. Significance of JAK2 and TET2 mutations in myelodysplastic syndromes. Blood Rev 2010;24:83-90.

      DOIPubMed
    • 34. Bejar R. Myelodysplastic syndromes diagnosis: what is the role of molecular testing? Curr Hematol Malig Rep 2015;10:282-91.

    • 35. Wakayama T, Maniwa Y, Ago H, Kakazu N, Abe T. A variant form of myelodysplastic syndrome with Ph- minor-BCR/ABL transcript. Int J Hematol 2001;74:58-63.

      DOIPubMed
    • 36. Avgerinou C, Alamanos Y, Zikos P, Lampropoulou P, Melachrinou M, Labropoulou V, Tavernarakis I, Aktypi A, Kaiafas P, Raptis C, Kouraklis A, Karakantza M, Symeonidis A. The incidence of myelodysplastic syndromes in Western Greece is increasing. Ann Hematol 2013;92:877-87.

      DOIPubMedPMC
    • 37. Lesesve JF, Troussard X, Bastard C, Hurst JP, Nouet D, Callat MP, Lenormand B, Piguet H, Flandrin G, Macintyre E. p190bcr/abl rearrangement in myelodysplastic syndromes: two reports and review of the literature. Br J Haematol 1996;95:372-5.

      DOIPubMed
    • 38. Nakamura K, Inaba T, Nishimura J, Morgan GJ, Hayashi Y, Hanada R, Yamamoto K, Wada H, Kawaguchi H, Miyashita T, Wiedemann LM, Mizutani S. Molecular analysis of BCR/ABL products in a case of myelodysplastic syndrome with late appearing Philadelphia chromosome. Br J Haematol 1991;78:130-2.

      DOIPubMed
    • 39. Kohno T, Amenomori T, Atogami S, Sasagawa I, Nakamura H, Kuriyama K, Tomonaga M. Progression from myelodysplastic syndrome to acute lymphoblastic leukaemia with Philadelphia chromosome and p190 BCR-ABL transcript. Br J Haematol 1996;93:389-91.

      DOIPubMed
    • 40. Katsuno M, Yamashita S, Sadamura S, Umemura T, Hirata J, Nishimura J, Nawata H. Late-appearing Philadelphia chromosome in a patient with acute nonlymphocytic leukaemia derived from myelodysplastic syndrome: detection of P210- and P190-type bcr/abl fusion gene transcripts at the leukaemic stage. Br J Haematol 1994;87:51-6.

      DOIPubMed
    • 41. Verhoef G, Meeus P, Stul M, Mecucci C, Cassiman JJ, Van Den Berghe H, Boogaerts M. Cytogenetic and molecular studies of the Philadelphia translocation in myelodysplastic syndromes. Report of two cases and review of the literature. Cancer Genet Cytogenet 1992;59:161-6.

      DOI
    • 42. Park SJ, Lee HW, Jeong SH, Park JS, Kim HC, Seok JY, Kim HJ, Cho SR. Acquisition of a BCR-ABL1 transcript in a patient with disease progression from MDS with fibrosis to AML with myelodysplasia-related changes. Ann Clin Lab Sci 2011;41:379-84.

    • 43. Onozawa M, Fukuhara T, Takahata M, Yamamoto Y, Miyake T, Maekawa I. A case of myelodysplastic syndrome developed blastic crisis of chronic myelogenous leukemia with acquisition of major BCR/ABL. Ann Hematol 2003;82:593-5.

      DOIPubMed
    • 44. Keung YK, Beaty M, Powell BL, Molnar I, Buss D, Pettenati M. Philadelphia chromosome positive myelodysplastic syndrome and acute myeloid leukemia-retrospective study and review of literature. Leuk Res 2004;28:579-86.

      DOIPubMed
    • 45. Zhang L, Bennett JM, Zhang X, Moscinski L, Ibarz-Pinilla J, List AF, Komrokji R. Uncommon of the uncommon: low-grade myelodysplastic syndrome evolving into chronic myelogenous leukemia. J Clin Oncol 2011;29:e434-6.

    • 46. Larripa I, Gutiérrez M, Giere I, Acevedo S, Bengió R, Slavutsky I. Complex karyotype with PH1 chromosome in myelodysplasia: cytogenetic and molecular studies. Leuk Lymphoma 2009;6:401-6.

      DOI
    • 47. Roth DG, Richman CM, Rowley JD. Chronic myelodysplastic syndrome (preleukemia) with the Philadelphia chromosome. Blood 1980;56:262-4.

    • 48. Smadja N, Krulik M, De Gramont A, Brissaud P, Debray J. Acquisition of a Philadelphia chromosome concomitant with transformation of a refractory anemia into an acute leukemia. Cancer 1985;55:1477-81.

      DOI
    • 49. Berrebi A, Bruck R, Shtalrid M, Chemke J. Philadelphia chromosome in idiopathic acquired sideroblastic anemia. Acta Haematol 1984;72:343-5.

      DOIPubMed
    • 50. Ohyashiki K, Ohyashiki JH, Raza A, Preisler HD, Sandberg AA. Phenylbutazone-induced myelodysplastic syndrome with Philadelphia translocation. Cancer Genet Cytogenet 1987;26:213-6.

      DOI

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