Cancer Genetics 208 (2015) 464–467
BRIEF COMMUNICATION
KMT2A (MLL)-MLLT1 rearrangement in blastic plasmacytoid dendritic cell neoplasm Naery Yang a, Jungwon Huh a, Wha Soon Chung a, Min-Sun Cho b, Kyung-Ha Ryu c, Hae-Sun Chung a,* a Department of Laboratory Medicine, Ewha Womans University School of Medicine, Seoul, Republic of Korea; b Department of Pathology, Ewha Womans University School of Medicine, Seoul, Republic of Korea; c Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Republic of Korea
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy characterized by CD4 and CD56 coexpression without apparent lineage commitment. The molecular pathogenesis of BPDCN has been studied in only a limited number of cases, and specific chromosomal aberrations are lacking thus far. KMT2A (MLL) rearrangements are observed in various types of pediatric and adult leukemia, but only one adult case report has so far showed KMT2A (MLL)-MLLT1 gene rearrangements in BPDCN. We present the first pediatric case of BPDCN with a KMT2A (MLL)-MLLT1 rearrangement confirmed by molecular study. The karyotype demonstrated a t(11;19)(q23;p13.3), trisomy 8, and trisomy 19 in all 20 metaphase cells analyzed: 48,XX,+8,t(11;19)(q23;p13.3),+19[20]. Fluorescence in situ hybridization analysis showed KMT2A (MLL) gene rearrangement in 83% of interphase cells. The KMT2A (MLL)-MLLT1 gene rearrangement was confirmed by multiplex reverse transcriptase polymerase chain reaction. We suggest that the pathogenesis of BPDCN could be associated with KMT2A (MLL) rearrangement (especially with KMT2A (MLL)-MLLT1) and further study on a larger number of cases is needed. Keywords Blastic plasmacytoid dendritic cell neoplasm, KMT2A (MLL), MLLT1, t(11;19) © 2015 Elsevier Inc. All rights reserved.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive malignancy arising from plasmacytoid dendritic cell precursors, and it is categorized among acute myeloid leukemia (AML) and related precursor neoplasms in the 2008 World Health Organization classification (1). BPDCN is characterized by CD4 and CD56 coexpression without apparent lymphoid or myeloid lineage commitment. BPDCN generally affects older adults and often follows a rapidly fatal course (1,2). Only a few pediatric BPDCN cases have been reported (1–3). In contrast to the poor outcome in adults, relatively favorable outcome has been shown in pediatric BPDCN patients treated with high-risk acute lymphoblastic leukemia (ALL)– like induction therapy regimens (2,3). The basis for the apparent disparity in clinical behavior between adult and pediatric BPDCN is not clear. The pathogenesis of BPDCN is not well understood, and little is currently known about the genetic features of this Received February 6, 2015; received in revised form April 13, 2015; accepted April 28, 2015. * Corresponding author. E-mail address: [email protected] 2210-7762/$ - see front matter © 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cancergen.2015.04.011
disease entity. KMT2A (MLL) rearrangements are observed in various types of pediatric or adult leukemias, such as ALL, AML, mixed-phenotype acute leukemia, and therapy-related leukemia (1,4–6), but the association between KMT2A (MLL) rearrangements and BPDCN has not been well documented. The KMT2A (MLL) gene on chromosome 11q23 can be rearranged with numerous different partner genes. Among the partner genes, the breakpoints on chromosome 19 are variable, and the breaks can occur at either p13.1 or p13.3: ELL at 19p13.1, MLLT1 at 19p13.3. To the best of our knowledge, only one adult BPDCN case with the t(11;19)(q23;p13) and KMT2A (MLL)-MLLT1 gene rearrangement has been reported (7). Here, we report the first pediatric BPDCN case with a t(11;19)(q23;p13.3) confirmed by molecular study.
Materials and methods Patient presentation An 8-year-old girl presented with fever for 2 days and easy bruising for a week. She had mild fatigue and petechiae on
KMT2A (MLL)-MLLT1 rearrangement in BPDCN
465
Figure 1 Morphologic and immunophenotypic characteristics of BPDCN in (A) bone marrow aspirate (Wright–Giemsa stain, × 400), (B) bone marrow biopsy (hematoxylin and eosin stain, × 400), and (C) flow cytometric profile of blasts coexpressing CD4/CD56. PE-Cy7 is a name (label) of a fluorochorome conjugate for flow cytometry. (Abbreviation: Cy, cyanine dye, PE, phycoerythrin, Q, quadrant) Circled section represents the cell-population which coexpresses CD4 and CD16/CD56.
both arms and legs, and no special medical history was noted. There was no skin lesion except petechiae. Complete blood cell counts showed normocytic normochromic anemia (hemoglobin concentration 10.3 g/dL), thrombocytopenia (38,000 cells/µL), and marked leukocytosis (88,000 cells/µL), with 95% blasts. Bone marrow examination revealed marked hypercellular marrow (100%), which consisted mostly of blasts with an increased number of megakaryocytes. The blasts were medium- to large-sized cells with eccentric round nuclei and fine chromatin. Some of them had microvacuoles in the cytoplasm and elongated agranular cytoplasm (Figure 1). Cytochemical stains for myeloperoxidase (MPO), Sudan black B, nonspecific esterase, and specific esterase were negative in the blasts. Flow cytometric analysis of the bone marrow aspirate revealed positivity for terminal deoxynucleotidyl transferase, CD33, CD15, CD64, CD56, CD4, CD117, and HLADR, and negativity for CD19, CD20, CD10, cytoplasmic CD22, cytoplasmic MPO, CD13, CD14, CD16, cytoplasmic CD3, CD2, CD3, CD5, CD7, and CD34. In particular, a population with CD4 and CD56 coexpression (44% of all nucleated cells) was noted (Figure 1). Immunohistochemical staining of the bone marrow biopsy was performed, which revealed that the blasts were positive for CD56 but negative for CD34, CD45, TdT, CD79a, CD20, CD3, and MPO. Taken together, these results led to a diagnosis of a leukemic manifestation of BPDCN. The patient received induction chemotherapy consisting of daunorubicin, vincristine, prednisolone, and cytarabine. Bone marrow examination at 1 month after diagnosis revealed complete remission, and the patient remained in remission for 5 months.
Karyotype analysis, fluorescence in situ hybridization, and molecular genetics For cytogenetic analysis, an unstimulated and short-term culture was performed using bone marrow aspirate and was described according to ISCN 2013 (8). Fluorescence in situ hybridization (FISH) analysis was performed using a variety of DNA probes, including MLL dual-color, break apart rearrangement probe (Abbott Laboratories, Abbott Park, IL, United States), according to the manufacturer’s instructions.
Multiplex, nested reverse transcriptase PCR was performed for the screening and detection of 28 chromosomal translocations using the HemaVision kit (DNA Technology, Research Park, Aarhus, Denmark).
Results The karyotype demonstrated t(11;19)(q23;p13.3), trisomy 8, and trisomy 19 in all 20 metaphase cells analyzed: 48,XX,+8,t(11;19)(q23;p13.3),+19[20] (Figure 2). FISH analysis showed KMT2A (MLL) gene rearrangement in 83% of interphase cells. DNA probes specific for BCR/ ABL1, RUNX1/RUNX1T1, PML/RARA, CBFB, EGR1/D5S721/ D5S23, CEP7/D7S486, ETV6, D20S108, TP53, p16, IgH break apart, and 6q21/6q23 showed normal hybridization signals in all interphase cells examined. The KMT2A (MLL)-MLLT1 gene rearrangement was confirmed by multiplex reverse transcriptase PCR using the HemaVision kit (DNA Technology, Research Park, Aarhus, Denmark).
Discussion Genetic aberrations of BPDCN have been studied in only a limited number of cases. Thus far, genetic mechanisms associated with BPDCN are not well understood. Chromosomal abnormalities and gene mutations associated with other myeloid and lymphoid neoplasms were identified in some BPDCN cases (2,9–16). Targeted exome sequencing recently identified recurrent mutations such as TET2, NRAS, TP53, ASXL1, and ATM (2,9–11). However, none were specific or diagnostic for BPDCN. In one study using conventional cytogenetic and FISH analyses, two-thirds of BPDCN had cytogenetic abnormalities at the time of diagnosis, and genomic imbalances (mostly losses) and complex chromosomal aberrations predominated (12). Karyotyping, FISH, and array comparative genomic hybridization studies have helped identify some recurrent breakpoints implicated in BPDCN. These include 4q34, 5q21q34, 6q23-qter, 7p12.2 (IKZF1), 9p13-p11 (CDKN2A/CDKN2B), 9q12-q31, 12p13 (CDKN1B), 13q12-31 (RB1), and 15q (2,13–15). Few BPDCN cases with 11q23 abnormalities have
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N. Yang et al.
Figure 2 A G-banded karyogram showing 48,XX,+8,t(11;19)(q23;p13.3),+19. The arrow toward chromosome 8 indicates gain of chromosome 8. The arrow toward chromosome 11 indicates abnormal chromosome 11 derived from t(11;19). The arrow toward chromosome 19 indicates gain of chromosome 19 and abnormal chromosome 19 derived from t(11;19).
been described; among those that have been reported are one t(9;11)(p21;q23) and a 11q23 deletion (16). To date, only one BPDCN case with a t(11;19)(q23;p13) has presented a KMT2A (MLL)-MLLT1 rearrangement confirmed by molecular studies (7). In that case, trisomy 8 was found, as it was in our case, and patients remained in remission to the last follow-up in both cases. In conclusion, we report the first pediatric case of BPDCN with a KMT2A (MLL) rearrangement here. We suggest that the pathogenesis of BPDCN could be associated with the KMT2A (MLL) rearrangement (especially KMT2A (MLL)MLLT1) and that further study on a larger number of cases is needed.
Acknowledgment This study was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (NRF-2012R1A1A2044138).
References 1. Facchetti F, Jones DM, Petrella T. Blastic plasmacytoid dendritic cell neoplasm. In: Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008:145–147. 2. Riaz W, Zhang L, Horna P, et al. Blastic plasmacytoid dendritic cell neoplasm: update on molecular biology, diagnosis, and therapy. Cancer Control 2014;21:279–289. 3. Jegalian AG, Buxbaum NP, Facchetti F, et al. Blastic plasmacytoid dendritic cell neoplasm in children: diagnostic features and clinical implications. Haematologica 2010;95:1873–1879. 4. Meyer C, Hofmann J, Burmeister T, et al. The MLL recombinome of acute leukemias in 2013. Leukemia 2013;27:2165–2176. 5. Yoo BJ, Nam MH, Sung HJ, et al. A case of therapy-related acute lymphoblastic leukemia with t(11;19)(q23;p13.3) and MLL/MLLT1 gene rearrangement. Korean J Lab Med 2011;31:13–17. 6. Naghashpour M, Lancet J, Moscinski L, et al. Mixed phenotype acute leukemia with t(11;19)(q23;p13.3)/MLL-MLLT1 (ENL), B/T-lymphoid type: a first case report. Am J Hematol 2010;85:451–454.
KMT2A (MLL)-MLLT1 rearrangement in BPDCN 7. Toya T, Nishimoto N, Koya J, et al. The first case of blastic plasmacytoid dendritic cell neoplasm with MLL-ENL rearrangement. Leuk Res 2012;36:117–118. 8. Shaffer LG, McGowan-Jordan J, Schmid M. ISCN 2013: An International System for Human Cytogenetic Nomenclature. Basel: Karger, 2013. 9. Alayed K, Patel KP, Konoplev S, et al. TET2 mutations, myelodysplastic features, and a distinct immunoprofile characterize blastic plasmacytoid dendritic cell neoplasm in the bone marrow. Am J Hematol 2013;88:1055–1061. 10. Menezes J, Acquadro F, Wiseman M, et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia 2014;28:823– 829. 11. Stenzinger A, Endris V, Pfarr N, et al. Targeted ultradeep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm. Oncotarget 2014;5:6404–6413.
467 12. Leroux D, Mugneret F, Callanan M, et al. CD4(+), CD56(+) DC2 acute leukemia is characterized by recurrent clonal chromosomal changes affecting six major targets: a study of 21 cases by the Groupe Francais de Cytogenetique Hematologique. Blood 2002;99:4154–4159. 13. Dijkman R, van Doorn R, Szuhai K, et al. Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities. Blood 2007;109:1720–1727. 14. Wiesner T, Obenauf AC, Cota C, et al. Alterations of the cell-cycle inhibitors p27KIP1 and p16INK4a are frequent in blastic plasmacytoid dendritic cell neoplasms. J Invest Dermatol 2010;130:1152–1157. 15. Lucioni M, Novara F, Fiandrino G, et al. Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion. Blood 2011;118:4591–44594. 16. Bueno C, Almeida J, Lucio P, et al. Incidence and characteristics of CD4(+)/HLA DRhi dendritic cell malignancies. Haematologica 2004;89:58–69.
BRIEF COMMUNICATION
KMT2A (MLL)-MLLT1 rearrangement in blastic plasmacytoid dendritic cell neoplasm Naery Yang a, Jungwon Huh a, Wha Soon Chung a, Min-Sun Cho b, Kyung-Ha Ryu c, Hae-Sun Chung a,* a Department of Laboratory Medicine, Ewha Womans University School of Medicine, Seoul, Republic of Korea; b Department of Pathology, Ewha Womans University School of Medicine, Seoul, Republic of Korea; c Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Republic of Korea
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy characterized by CD4 and CD56 coexpression without apparent lineage commitment. The molecular pathogenesis of BPDCN has been studied in only a limited number of cases, and specific chromosomal aberrations are lacking thus far. KMT2A (MLL) rearrangements are observed in various types of pediatric and adult leukemia, but only one adult case report has so far showed KMT2A (MLL)-MLLT1 gene rearrangements in BPDCN. We present the first pediatric case of BPDCN with a KMT2A (MLL)-MLLT1 rearrangement confirmed by molecular study. The karyotype demonstrated a t(11;19)(q23;p13.3), trisomy 8, and trisomy 19 in all 20 metaphase cells analyzed: 48,XX,+8,t(11;19)(q23;p13.3),+19[20]. Fluorescence in situ hybridization analysis showed KMT2A (MLL) gene rearrangement in 83% of interphase cells. The KMT2A (MLL)-MLLT1 gene rearrangement was confirmed by multiplex reverse transcriptase polymerase chain reaction. We suggest that the pathogenesis of BPDCN could be associated with KMT2A (MLL) rearrangement (especially with KMT2A (MLL)-MLLT1) and further study on a larger number of cases is needed. Keywords Blastic plasmacytoid dendritic cell neoplasm, KMT2A (MLL), MLLT1, t(11;19) © 2015 Elsevier Inc. All rights reserved.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive malignancy arising from plasmacytoid dendritic cell precursors, and it is categorized among acute myeloid leukemia (AML) and related precursor neoplasms in the 2008 World Health Organization classification (1). BPDCN is characterized by CD4 and CD56 coexpression without apparent lymphoid or myeloid lineage commitment. BPDCN generally affects older adults and often follows a rapidly fatal course (1,2). Only a few pediatric BPDCN cases have been reported (1–3). In contrast to the poor outcome in adults, relatively favorable outcome has been shown in pediatric BPDCN patients treated with high-risk acute lymphoblastic leukemia (ALL)– like induction therapy regimens (2,3). The basis for the apparent disparity in clinical behavior between adult and pediatric BPDCN is not clear. The pathogenesis of BPDCN is not well understood, and little is currently known about the genetic features of this Received February 6, 2015; received in revised form April 13, 2015; accepted April 28, 2015. * Corresponding author. E-mail address: [email protected] 2210-7762/$ - see front matter © 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cancergen.2015.04.011
disease entity. KMT2A (MLL) rearrangements are observed in various types of pediatric or adult leukemias, such as ALL, AML, mixed-phenotype acute leukemia, and therapy-related leukemia (1,4–6), but the association between KMT2A (MLL) rearrangements and BPDCN has not been well documented. The KMT2A (MLL) gene on chromosome 11q23 can be rearranged with numerous different partner genes. Among the partner genes, the breakpoints on chromosome 19 are variable, and the breaks can occur at either p13.1 or p13.3: ELL at 19p13.1, MLLT1 at 19p13.3. To the best of our knowledge, only one adult BPDCN case with the t(11;19)(q23;p13) and KMT2A (MLL)-MLLT1 gene rearrangement has been reported (7). Here, we report the first pediatric BPDCN case with a t(11;19)(q23;p13.3) confirmed by molecular study.
Materials and methods Patient presentation An 8-year-old girl presented with fever for 2 days and easy bruising for a week. She had mild fatigue and petechiae on
KMT2A (MLL)-MLLT1 rearrangement in BPDCN
465
Figure 1 Morphologic and immunophenotypic characteristics of BPDCN in (A) bone marrow aspirate (Wright–Giemsa stain, × 400), (B) bone marrow biopsy (hematoxylin and eosin stain, × 400), and (C) flow cytometric profile of blasts coexpressing CD4/CD56. PE-Cy7 is a name (label) of a fluorochorome conjugate for flow cytometry. (Abbreviation: Cy, cyanine dye, PE, phycoerythrin, Q, quadrant) Circled section represents the cell-population which coexpresses CD4 and CD16/CD56.
both arms and legs, and no special medical history was noted. There was no skin lesion except petechiae. Complete blood cell counts showed normocytic normochromic anemia (hemoglobin concentration 10.3 g/dL), thrombocytopenia (38,000 cells/µL), and marked leukocytosis (88,000 cells/µL), with 95% blasts. Bone marrow examination revealed marked hypercellular marrow (100%), which consisted mostly of blasts with an increased number of megakaryocytes. The blasts were medium- to large-sized cells with eccentric round nuclei and fine chromatin. Some of them had microvacuoles in the cytoplasm and elongated agranular cytoplasm (Figure 1). Cytochemical stains for myeloperoxidase (MPO), Sudan black B, nonspecific esterase, and specific esterase were negative in the blasts. Flow cytometric analysis of the bone marrow aspirate revealed positivity for terminal deoxynucleotidyl transferase, CD33, CD15, CD64, CD56, CD4, CD117, and HLADR, and negativity for CD19, CD20, CD10, cytoplasmic CD22, cytoplasmic MPO, CD13, CD14, CD16, cytoplasmic CD3, CD2, CD3, CD5, CD7, and CD34. In particular, a population with CD4 and CD56 coexpression (44% of all nucleated cells) was noted (Figure 1). Immunohistochemical staining of the bone marrow biopsy was performed, which revealed that the blasts were positive for CD56 but negative for CD34, CD45, TdT, CD79a, CD20, CD3, and MPO. Taken together, these results led to a diagnosis of a leukemic manifestation of BPDCN. The patient received induction chemotherapy consisting of daunorubicin, vincristine, prednisolone, and cytarabine. Bone marrow examination at 1 month after diagnosis revealed complete remission, and the patient remained in remission for 5 months.
Karyotype analysis, fluorescence in situ hybridization, and molecular genetics For cytogenetic analysis, an unstimulated and short-term culture was performed using bone marrow aspirate and was described according to ISCN 2013 (8). Fluorescence in situ hybridization (FISH) analysis was performed using a variety of DNA probes, including MLL dual-color, break apart rearrangement probe (Abbott Laboratories, Abbott Park, IL, United States), according to the manufacturer’s instructions.
Multiplex, nested reverse transcriptase PCR was performed for the screening and detection of 28 chromosomal translocations using the HemaVision kit (DNA Technology, Research Park, Aarhus, Denmark).
Results The karyotype demonstrated t(11;19)(q23;p13.3), trisomy 8, and trisomy 19 in all 20 metaphase cells analyzed: 48,XX,+8,t(11;19)(q23;p13.3),+19[20] (Figure 2). FISH analysis showed KMT2A (MLL) gene rearrangement in 83% of interphase cells. DNA probes specific for BCR/ ABL1, RUNX1/RUNX1T1, PML/RARA, CBFB, EGR1/D5S721/ D5S23, CEP7/D7S486, ETV6, D20S108, TP53, p16, IgH break apart, and 6q21/6q23 showed normal hybridization signals in all interphase cells examined. The KMT2A (MLL)-MLLT1 gene rearrangement was confirmed by multiplex reverse transcriptase PCR using the HemaVision kit (DNA Technology, Research Park, Aarhus, Denmark).
Discussion Genetic aberrations of BPDCN have been studied in only a limited number of cases. Thus far, genetic mechanisms associated with BPDCN are not well understood. Chromosomal abnormalities and gene mutations associated with other myeloid and lymphoid neoplasms were identified in some BPDCN cases (2,9–16). Targeted exome sequencing recently identified recurrent mutations such as TET2, NRAS, TP53, ASXL1, and ATM (2,9–11). However, none were specific or diagnostic for BPDCN. In one study using conventional cytogenetic and FISH analyses, two-thirds of BPDCN had cytogenetic abnormalities at the time of diagnosis, and genomic imbalances (mostly losses) and complex chromosomal aberrations predominated (12). Karyotyping, FISH, and array comparative genomic hybridization studies have helped identify some recurrent breakpoints implicated in BPDCN. These include 4q34, 5q21q34, 6q23-qter, 7p12.2 (IKZF1), 9p13-p11 (CDKN2A/CDKN2B), 9q12-q31, 12p13 (CDKN1B), 13q12-31 (RB1), and 15q (2,13–15). Few BPDCN cases with 11q23 abnormalities have
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N. Yang et al.
Figure 2 A G-banded karyogram showing 48,XX,+8,t(11;19)(q23;p13.3),+19. The arrow toward chromosome 8 indicates gain of chromosome 8. The arrow toward chromosome 11 indicates abnormal chromosome 11 derived from t(11;19). The arrow toward chromosome 19 indicates gain of chromosome 19 and abnormal chromosome 19 derived from t(11;19).
been described; among those that have been reported are one t(9;11)(p21;q23) and a 11q23 deletion (16). To date, only one BPDCN case with a t(11;19)(q23;p13) has presented a KMT2A (MLL)-MLLT1 rearrangement confirmed by molecular studies (7). In that case, trisomy 8 was found, as it was in our case, and patients remained in remission to the last follow-up in both cases. In conclusion, we report the first pediatric case of BPDCN with a KMT2A (MLL) rearrangement here. We suggest that the pathogenesis of BPDCN could be associated with the KMT2A (MLL) rearrangement (especially KMT2A (MLL)MLLT1) and that further study on a larger number of cases is needed.
Acknowledgment This study was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (NRF-2012R1A1A2044138).
References 1. Facchetti F, Jones DM, Petrella T. Blastic plasmacytoid dendritic cell neoplasm. In: Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008:145–147. 2. Riaz W, Zhang L, Horna P, et al. Blastic plasmacytoid dendritic cell neoplasm: update on molecular biology, diagnosis, and therapy. Cancer Control 2014;21:279–289. 3. Jegalian AG, Buxbaum NP, Facchetti F, et al. Blastic plasmacytoid dendritic cell neoplasm in children: diagnostic features and clinical implications. Haematologica 2010;95:1873–1879. 4. Meyer C, Hofmann J, Burmeister T, et al. The MLL recombinome of acute leukemias in 2013. Leukemia 2013;27:2165–2176. 5. Yoo BJ, Nam MH, Sung HJ, et al. A case of therapy-related acute lymphoblastic leukemia with t(11;19)(q23;p13.3) and MLL/MLLT1 gene rearrangement. Korean J Lab Med 2011;31:13–17. 6. Naghashpour M, Lancet J, Moscinski L, et al. Mixed phenotype acute leukemia with t(11;19)(q23;p13.3)/MLL-MLLT1 (ENL), B/T-lymphoid type: a first case report. Am J Hematol 2010;85:451–454.
KMT2A (MLL)-MLLT1 rearrangement in BPDCN 7. Toya T, Nishimoto N, Koya J, et al. The first case of blastic plasmacytoid dendritic cell neoplasm with MLL-ENL rearrangement. Leuk Res 2012;36:117–118. 8. Shaffer LG, McGowan-Jordan J, Schmid M. ISCN 2013: An International System for Human Cytogenetic Nomenclature. Basel: Karger, 2013. 9. Alayed K, Patel KP, Konoplev S, et al. TET2 mutations, myelodysplastic features, and a distinct immunoprofile characterize blastic plasmacytoid dendritic cell neoplasm in the bone marrow. Am J Hematol 2013;88:1055–1061. 10. Menezes J, Acquadro F, Wiseman M, et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia 2014;28:823– 829. 11. Stenzinger A, Endris V, Pfarr N, et al. Targeted ultradeep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm. Oncotarget 2014;5:6404–6413.
467 12. Leroux D, Mugneret F, Callanan M, et al. CD4(+), CD56(+) DC2 acute leukemia is characterized by recurrent clonal chromosomal changes affecting six major targets: a study of 21 cases by the Groupe Francais de Cytogenetique Hematologique. Blood 2002;99:4154–4159. 13. Dijkman R, van Doorn R, Szuhai K, et al. Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities. Blood 2007;109:1720–1727. 14. Wiesner T, Obenauf AC, Cota C, et al. Alterations of the cell-cycle inhibitors p27KIP1 and p16INK4a are frequent in blastic plasmacytoid dendritic cell neoplasms. J Invest Dermatol 2010;130:1152–1157. 15. Lucioni M, Novara F, Fiandrino G, et al. Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion. Blood 2011;118:4591–44594. 16. Bueno C, Almeida J, Lucio P, et al. Incidence and characteristics of CD4(+)/HLA DRhi dendritic cell malignancies. Haematologica 2004;89:58–69.
