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Correspondence To the editor: Lysine-specific demethylase 1 (LSD1) in hematopoietic and lymphoid neoplasms Recently, inhibition of lysine-specific demethylase 1 (LSD1) has gained attention as a potential novel treatment in acute myeloid leukemia (AML).1-3 However, expression in other hematologic neoplasms has not been examined. LSD1 is a central epigenetic regulator of chromatin, acting in concert with many different activating and repressive histone-modifying complexes.4 It regulates self-renewal and differentiation in human embryonic stem cells5 and is overexpressed in a wide variety of human neoplasms.6 LSD1 depletion disrupts hematopoietic differentiation, and LSD1 has been shown to play a pivotal role in the maintenance of hematopoietic stem cells and differentiation of granulopoiesis, thrombopoiesis, and erythropoiesis.7 In murine leukemia models, targeting of LSD1 via tranylcypromine analogs abrogated oncogenic potential and induced differentiation of tumor cells. Inhibition of LSD1 was effective in unlocking the all-trans-retinoic acid–driven therapeutic response in non-acute promyelocytic leukemia AML.3 To widen the range of hematologic and lymphatic malignancies that may be targeted by using LSD1 inhibitors, we examined the expression of LSD1 in normal, reactive, and neoplastic diseases in bone marrow trephine biopsies (n 5 197) as well as lymphoid neoplasms in biopsies from lymphatic tissues (n 5 354). Bone marrow from patients with a completely normal blood count (biopsy obtained for staging purpose) were mostly negative for LSD1 (1 [6.7%] of 15) (Table 1), whereas LSD1 was expressed in the majority of reactive bone marrow samples, especially in erythroid cells and megakaryopoiesis (18 [66.7%] of 27). In myeloproliferative neoplasms, excluding chronic myelogenous leukemia, LSD1 was expressed in half the patients (26 [50.0%] of 52), mainly in megakaryocytes, in erythroid cells and, to a lesser degree, in early myeloid cells. In chronic myelogenous leukemia, LSD1 was expressed in one third of the patients (6 [31.6%] of 19), primarily in myeloid cells and megakaryocytes. Further, in myelodysplastic syndromes, more than half the patients (9 [56.3%] of 16) demonstrated nuclear expression in dysplastic megakaryocytes and early erythroid cells. Atypical myelocytic and monocytic cells as well as megakaryocytes showed LSD1 expression in chronic myelomonocytic leukemia (5 [50.0%] of 10). LSD1 was expressed frequently in a blast-specific nuclear pattern in primary and secondary AMLs (21 [46.7%] of 45). LSD1 expression in lymphoid malignancies was observed in 123 of 354 patients or 34.7% overall. Low-grade B-cell non-Hodgkin lymphomas (B-NHLs) expressed LSD1 less often (19 [12.9%] of 147) than did high-grade B-NHLs (52 [39.7%] of 131) (Pearson x2 test P , .001) (Table 1). Both, T-cell NHLs (14 [66.7%] of 21) and Hodgkin lymphomas (38 [69.1%] of 55) showed LSD1 expression more frequently than B-NHLs (71 [25.5%] of 278) (Pearson x2 test P , .001 for both). On the basis of these results, we conclude that in addition to in AML, LSD1 is overexpressed in myeloproliferative neoplasms, chronic myelomonocytic leukemia, and myelodysplastic syndromes, possibly widening the spectrum of diseases amenable to LSD1 inhibitor therapy. Expression in reactive hematopoiesis needs to be considered when using LSD1 inhibitors to treat these diseases, consistent with concerns raised by other investigators.7,8 However, transient cytopenias
BLOOD, 3 JULY 2014 x VOLUME 124, NUMBER 1
may still be manageable because more established cytotoxic therapies also affect hematopoiesis. Whether patients with the above-mentioned diseases would benefit from treatment with LSD1 inhibitors requires further investigation. Dennis Niebel Institute of Pathology, University of Bonn, Bonn, Germany Jutta Kirfel Institute of Pathology, University of Bonn, Bonn, Germany Viktor Janzen Division of Hematology and Oncology, Department of Internal Medicine III, University of Bonn, Bonn, Germany Tobias Holler ¨ Institute for Medical Biometry, Computer Science and Epidemiology, University of Bonn, Bonn, Germany Michael Majores Heinz-Werner-Seifert-Institute of Dermatopathology, Bonn, Germany Ines Gutgemann ¨ Institute of Pathology, University of Bonn, Bonn, Germany Contribution: D.N. analyzed data, wrote the manuscript, and collected data; I.G. designed the study, wrote the manuscript, and collected data; J.K. performed the fluorescence in situ hybridization analysis; T.H. performed the statistical analysis; M.M. performed data analysis and collected data; and V.J. analyzed the clinical data and wrote the manuscript. Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Ines G utgemann, ¨ Department of Pathology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany; e-mail: [email protected].
References 1. Dent SY, Chandra J. The lasting influence of LSD1 in the blood. Elife. 2013; 2:e00963. 2. Harris WJ, Huang X, Lynch JT, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012; 21(4):473-487. 3. Schenk T, Chen WC, Gollner ¨ S, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 2012;18(4):605-611. 4. Rudolph T, Beuch S, Reuter G. Lysine-specific histone demethylase LSD1 and the dynamic control of chromatin. Biol Chem. 2013;394(8): 1019-1028. 5. Adamo A, Sese´ B, Boue S, et al. LSD1 regulates the balance between selfrenewal and differentiation in human embryonic stem cells. Nat Cell Biol. 2011; 13(6):652-659. 6. Amente S, Lania L, Majello B. The histone LSD1 demethylase in stemness and cancer transcription programs. Biochim Biophys Acta. 2013;1829(10): 981-986.
151
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BLOOD, 3 JULY 2014 x VOLUME 124, NUMBER 1
CORRESPONDENCE
Table 1. LSD1 expression in normal and reactive hematopoiesis and hematopoietic and lymphoid neoplasms Intensity of expression ICD-O-3
No. Negative
%
Positive
%
Mean age (y)
SD
F
%
M
%
Hematopoiesis and hematopoietic neoplasms Normal
NA
15
14
93.3
1
6.7
49.6
18.4
8 53.3
7
46.7
Reactive
NA
27
9
33.3
18
66.7
61.6
15.9
8 29.6
19
70.4
MPN
9875/3 CML
19
13
68.4
6
31.6
61.6
11.2
9 47.4
10
52.6
9
6
66.7
3
33.3
60.1
12.2
4 44.4
5
55.6
9961/3 PMF
31
13
41.9
18
58.1
65.2
14.5
16 51.6
15
48.4
9962/3 ET
12
7
58.3
5
41.7
68.2
11.6
7 58.3
5
41.7
9950/3 PV
Total
71
39
54.9
32
45.1
64.1
13.0
36 50.7
35
49.3
MDS/MPN
9945/3 CMML
10
5
50.0
5
50.0
69.4
6.9
3 30.0
7
70.0
MDS
Various, RA, RARS, RAEB I, RAEB II
16
7
43.8
9
56.3
66.8
13.3
4 25.0
12
75.0
AML
Various, AML with recurrent genetic abnormalities
7
3
42.9
4
57.1
54.9
13.9
4 57.1
3
42.9
9895/3 AML with myelodysplasia related changes
18
8
44.4
10
55.6
69.2
9.2
6 33.3
12
66.7
9861/3 AML NOS
13
6
46.2
7
53.8
64.1
13.3
9 69.2
4
30.8
7
7
100.0
0
0.0
68.9
5.4
2 28.6
5
71.4
Total
45
24
53.3
21
46.7
65.4
11.7
21 46.7
24
53.3
9811/3 B-ALL
11
5
45.5
6
54.5
54.6
19.5
2 18.2
9
81.8
9837/3 T-ALL
2
0
0.0
2
100.0
47.0
26.9
0
2 100.0
13
5
38.5
8
61.5
53.5
19.6
2 15.4
NA, blast crisis from MPN ALL
Total
0.0
11
84.6
Lymphoid neoplasms Low-grade B-NHL
9823/3 CLL/SLL
36
36
100.0
0
0.0
66.8
10.7
12 33.3
24
66.7
9699/3 Marginal zone lymphoma
21
16
76.2
5
23.8
64.2
12.6
10 47.6
11
52.4
9690/3 Follicular lymphoma, grade 1,2
57
54
94.7
3
5.3
60.6
11.8
29 50.9
28
49.1
9673/3 Mantle cell lymphoma
33
22
66.7
11
33.3
68.2
8.8
8 24.2
25
75.8
147
128
87.1
19
12.9
64.3
11.4
59 40.1
88
59.9
Total High-grade B-NHL 9690/3 Follicular lymphoma, grade 3a,3b 9680/3 DLBCL NOS 9687/3 Burkitt lymphoma B-NHL
20
15
75.0
5
25.0
59.7
16.7
14 70.0
6
30.0
102
63
61.8
39
38.2
62.2
17.3
48 47.1
54
52.9
9
1
11.1
8
88.9
56.7
27.5
3 33.3
6
66.7
Total
131
79
60.3
52
39.7
61.4
17.9
65 49.6
66
50.4
Total
278
207
74.5
71
25.5
63.0
14.9 124 44.6 154
55.4
9705/3 AITL
8
2
25.0
6
75.0
66.6
13.3
4 50.0
4
50.0
9714/3 ALCL
6
0
0.0
6
100.0
44.2
26.2
2 33.3
4
66.7
T-NHL
9705/3 PTCL NOS
7
5
71.4
2
28.6
76.7
6.8
5 71.4
2
28.6
Total
21
7
33.3
14
66.7
62.5
16.7
11 52.4
10
47.6
9663/3 Nodular sclerosing type
36
14
38.9
22
61.1
34.6
19.0
21 58.3
15
41.7
9652/3 Mixed cellularity subtype
10
2
20.0
8
80.0
31,8
14.6
5 50.0
5
50.0
HL
9651/3 Lymphocyte-rich/lymphocyte-predominant Total
9
1
11.1
8
88.9
50.7
23.6
5 55.6
4
44.4
55
17
30.9
38
69.1
36.8
19.8
31 56.4
24
43.6
To determine LSD1 expression in hematopoiesis and hematopoietic neoplasms, bone marrow trephine biopsies were decalcified and immunostained by using a monoclonal anti-mouse antibody against LSD1 (1:500; Novus Biologicals, Littleton, CO). Intensity of expression was assessed as either none or background (negative) or moderate or strong (positive). Expression was positive in myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS), normal bone marrow, and reactive bone marrow if 1 to 3 lineages showed intensive expression, which was most often observed in the erythroid and megakaryocytic lineage. In acute leukemias, blasts only were scored. To determine LSD1 expression in lymphoid neoplasms, tissue microarrays of lymphoid tissues were immunostained with anti-mouse antibody against LSD1 (1:2000; Novus Biologicals). Samples with expression in less than 10% of tumor cells were scored as negative; moderate or strong staining in more than 10% of tumor cells was scored positive. Tissue microarrays were constructed from lymphoma tissue samples reclassified according the World Health Organization 2008 classification and were obtained from the archives of the Institute of Pathology at the University of Bonn as described.9 LSD1 was expressed in 75 (48.4%) of 155 hematopoietic neoplasms but in only 123 (34.7%) of 354 lymphoid neoplasms (Pearson x2 test P , .004). Statistically significant differences were also found in expression of normal and reactive bone marrow (Fisher’s exact test P , .001) and normal and neoplastic bone marrow (Fisher’s exact test, P , .002). Among lymphoid neoplasms, there was a significant difference between high-grade and low-grade B-NHLs (Pearson x2 test P , .001). Expression in B-NHLs combined differed from T-cell NHLs (T-NHLs) as well as from Hodgkin lymphomas (HLs) (Pearson x2 test, P , .001 in both cases). All calculations were performed by using SPSS Statistics for Windows, Version 20 (IBM, Armonk, NY). AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; ALL, acute lymphoblastic leukemia; B-ALL, B-cell ALL; CLL, chronic lymphocytic leukemia, B-cell type; CML, chronic myelogenous leukemia; CMML, chronic myelomonocytic leukemia; DLBCL, diffuse large B-cell lymphoma; ET, essential thrombocythemia; F, female; ICD-O-03, International Classification of Diseases-Oncology, third edition; M, male; NA, not applicable; NOS, not otherwise specified; PMF, primary myelofibrosis; PTCL, peripheral T-cell-lymphoma; PV, polycythemia vera; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RARS, refractory anemia with ringed sideroblasts; SLL, small lymphocytic lymphoma; SD, standard deviation; T-ALL, T-cell ALL.
7. Kerenyi MA, Shao Z, Hsu YJ, et al. Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation. Elife. 2013;2:e00633.
9. Khristi J, Mey U, Kirfel J, Schmidt-Wolf IG, Gutgemann ¨ I. Sequential Hodgkin’s and non-Hodgkin’s lymphoma in non-immunocompromised patients. Ann Hematol. 2013;92(11):1565-1567.
8. Sprussel ¨ A, Schulte JH, Weber S, et al. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia. 2012;26(9):2039-2051.
© 2014 by The American Society of Hematology
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2014 124: 151-152 doi:10.1182/blood-2014-04-569525
Lysine-specific demethylase 1 (LSD1) in hematopoietic and lymphoid neoplasms Dennis Niebel, Jutta Kirfel, Viktor Janzen, Tobias Höller, Michael Majores and Ines Gütgemann
Updated information and services can be found at: http://www.bloodjournal.org/content/124/1/151.full.html Articles on similar topics can be found in the following Blood collections Hematopoiesis and Stem Cells (3325 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
Correspondence To the editor: Lysine-specific demethylase 1 (LSD1) in hematopoietic and lymphoid neoplasms Recently, inhibition of lysine-specific demethylase 1 (LSD1) has gained attention as a potential novel treatment in acute myeloid leukemia (AML).1-3 However, expression in other hematologic neoplasms has not been examined. LSD1 is a central epigenetic regulator of chromatin, acting in concert with many different activating and repressive histone-modifying complexes.4 It regulates self-renewal and differentiation in human embryonic stem cells5 and is overexpressed in a wide variety of human neoplasms.6 LSD1 depletion disrupts hematopoietic differentiation, and LSD1 has been shown to play a pivotal role in the maintenance of hematopoietic stem cells and differentiation of granulopoiesis, thrombopoiesis, and erythropoiesis.7 In murine leukemia models, targeting of LSD1 via tranylcypromine analogs abrogated oncogenic potential and induced differentiation of tumor cells. Inhibition of LSD1 was effective in unlocking the all-trans-retinoic acid–driven therapeutic response in non-acute promyelocytic leukemia AML.3 To widen the range of hematologic and lymphatic malignancies that may be targeted by using LSD1 inhibitors, we examined the expression of LSD1 in normal, reactive, and neoplastic diseases in bone marrow trephine biopsies (n 5 197) as well as lymphoid neoplasms in biopsies from lymphatic tissues (n 5 354). Bone marrow from patients with a completely normal blood count (biopsy obtained for staging purpose) were mostly negative for LSD1 (1 [6.7%] of 15) (Table 1), whereas LSD1 was expressed in the majority of reactive bone marrow samples, especially in erythroid cells and megakaryopoiesis (18 [66.7%] of 27). In myeloproliferative neoplasms, excluding chronic myelogenous leukemia, LSD1 was expressed in half the patients (26 [50.0%] of 52), mainly in megakaryocytes, in erythroid cells and, to a lesser degree, in early myeloid cells. In chronic myelogenous leukemia, LSD1 was expressed in one third of the patients (6 [31.6%] of 19), primarily in myeloid cells and megakaryocytes. Further, in myelodysplastic syndromes, more than half the patients (9 [56.3%] of 16) demonstrated nuclear expression in dysplastic megakaryocytes and early erythroid cells. Atypical myelocytic and monocytic cells as well as megakaryocytes showed LSD1 expression in chronic myelomonocytic leukemia (5 [50.0%] of 10). LSD1 was expressed frequently in a blast-specific nuclear pattern in primary and secondary AMLs (21 [46.7%] of 45). LSD1 expression in lymphoid malignancies was observed in 123 of 354 patients or 34.7% overall. Low-grade B-cell non-Hodgkin lymphomas (B-NHLs) expressed LSD1 less often (19 [12.9%] of 147) than did high-grade B-NHLs (52 [39.7%] of 131) (Pearson x2 test P , .001) (Table 1). Both, T-cell NHLs (14 [66.7%] of 21) and Hodgkin lymphomas (38 [69.1%] of 55) showed LSD1 expression more frequently than B-NHLs (71 [25.5%] of 278) (Pearson x2 test P , .001 for both). On the basis of these results, we conclude that in addition to in AML, LSD1 is overexpressed in myeloproliferative neoplasms, chronic myelomonocytic leukemia, and myelodysplastic syndromes, possibly widening the spectrum of diseases amenable to LSD1 inhibitor therapy. Expression in reactive hematopoiesis needs to be considered when using LSD1 inhibitors to treat these diseases, consistent with concerns raised by other investigators.7,8 However, transient cytopenias
BLOOD, 3 JULY 2014 x VOLUME 124, NUMBER 1
may still be manageable because more established cytotoxic therapies also affect hematopoiesis. Whether patients with the above-mentioned diseases would benefit from treatment with LSD1 inhibitors requires further investigation. Dennis Niebel Institute of Pathology, University of Bonn, Bonn, Germany Jutta Kirfel Institute of Pathology, University of Bonn, Bonn, Germany Viktor Janzen Division of Hematology and Oncology, Department of Internal Medicine III, University of Bonn, Bonn, Germany Tobias Holler ¨ Institute for Medical Biometry, Computer Science and Epidemiology, University of Bonn, Bonn, Germany Michael Majores Heinz-Werner-Seifert-Institute of Dermatopathology, Bonn, Germany Ines Gutgemann ¨ Institute of Pathology, University of Bonn, Bonn, Germany Contribution: D.N. analyzed data, wrote the manuscript, and collected data; I.G. designed the study, wrote the manuscript, and collected data; J.K. performed the fluorescence in situ hybridization analysis; T.H. performed the statistical analysis; M.M. performed data analysis and collected data; and V.J. analyzed the clinical data and wrote the manuscript. Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Ines G utgemann, ¨ Department of Pathology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany; e-mail: [email protected].
References 1. Dent SY, Chandra J. The lasting influence of LSD1 in the blood. Elife. 2013; 2:e00963. 2. Harris WJ, Huang X, Lynch JT, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012; 21(4):473-487. 3. Schenk T, Chen WC, Gollner ¨ S, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 2012;18(4):605-611. 4. Rudolph T, Beuch S, Reuter G. Lysine-specific histone demethylase LSD1 and the dynamic control of chromatin. Biol Chem. 2013;394(8): 1019-1028. 5. Adamo A, Sese´ B, Boue S, et al. LSD1 regulates the balance between selfrenewal and differentiation in human embryonic stem cells. Nat Cell Biol. 2011; 13(6):652-659. 6. Amente S, Lania L, Majello B. The histone LSD1 demethylase in stemness and cancer transcription programs. Biochim Biophys Acta. 2013;1829(10): 981-986.
151
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BLOOD, 3 JULY 2014 x VOLUME 124, NUMBER 1
CORRESPONDENCE
Table 1. LSD1 expression in normal and reactive hematopoiesis and hematopoietic and lymphoid neoplasms Intensity of expression ICD-O-3
No. Negative
%
Positive
%
Mean age (y)
SD
F
%
M
%
Hematopoiesis and hematopoietic neoplasms Normal
NA
15
14
93.3
1
6.7
49.6
18.4
8 53.3
7
46.7
Reactive
NA
27
9
33.3
18
66.7
61.6
15.9
8 29.6
19
70.4
MPN
9875/3 CML
19
13
68.4
6
31.6
61.6
11.2
9 47.4
10
52.6
9
6
66.7
3
33.3
60.1
12.2
4 44.4
5
55.6
9961/3 PMF
31
13
41.9
18
58.1
65.2
14.5
16 51.6
15
48.4
9962/3 ET
12
7
58.3
5
41.7
68.2
11.6
7 58.3
5
41.7
9950/3 PV
Total
71
39
54.9
32
45.1
64.1
13.0
36 50.7
35
49.3
MDS/MPN
9945/3 CMML
10
5
50.0
5
50.0
69.4
6.9
3 30.0
7
70.0
MDS
Various, RA, RARS, RAEB I, RAEB II
16
7
43.8
9
56.3
66.8
13.3
4 25.0
12
75.0
AML
Various, AML with recurrent genetic abnormalities
7
3
42.9
4
57.1
54.9
13.9
4 57.1
3
42.9
9895/3 AML with myelodysplasia related changes
18
8
44.4
10
55.6
69.2
9.2
6 33.3
12
66.7
9861/3 AML NOS
13
6
46.2
7
53.8
64.1
13.3
9 69.2
4
30.8
7
7
100.0
0
0.0
68.9
5.4
2 28.6
5
71.4
Total
45
24
53.3
21
46.7
65.4
11.7
21 46.7
24
53.3
9811/3 B-ALL
11
5
45.5
6
54.5
54.6
19.5
2 18.2
9
81.8
9837/3 T-ALL
2
0
0.0
2
100.0
47.0
26.9
0
2 100.0
13
5
38.5
8
61.5
53.5
19.6
2 15.4
NA, blast crisis from MPN ALL
Total
0.0
11
84.6
Lymphoid neoplasms Low-grade B-NHL
9823/3 CLL/SLL
36
36
100.0
0
0.0
66.8
10.7
12 33.3
24
66.7
9699/3 Marginal zone lymphoma
21
16
76.2
5
23.8
64.2
12.6
10 47.6
11
52.4
9690/3 Follicular lymphoma, grade 1,2
57
54
94.7
3
5.3
60.6
11.8
29 50.9
28
49.1
9673/3 Mantle cell lymphoma
33
22
66.7
11
33.3
68.2
8.8
8 24.2
25
75.8
147
128
87.1
19
12.9
64.3
11.4
59 40.1
88
59.9
Total High-grade B-NHL 9690/3 Follicular lymphoma, grade 3a,3b 9680/3 DLBCL NOS 9687/3 Burkitt lymphoma B-NHL
20
15
75.0
5
25.0
59.7
16.7
14 70.0
6
30.0
102
63
61.8
39
38.2
62.2
17.3
48 47.1
54
52.9
9
1
11.1
8
88.9
56.7
27.5
3 33.3
6
66.7
Total
131
79
60.3
52
39.7
61.4
17.9
65 49.6
66
50.4
Total
278
207
74.5
71
25.5
63.0
14.9 124 44.6 154
55.4
9705/3 AITL
8
2
25.0
6
75.0
66.6
13.3
4 50.0
4
50.0
9714/3 ALCL
6
0
0.0
6
100.0
44.2
26.2
2 33.3
4
66.7
T-NHL
9705/3 PTCL NOS
7
5
71.4
2
28.6
76.7
6.8
5 71.4
2
28.6
Total
21
7
33.3
14
66.7
62.5
16.7
11 52.4
10
47.6
9663/3 Nodular sclerosing type
36
14
38.9
22
61.1
34.6
19.0
21 58.3
15
41.7
9652/3 Mixed cellularity subtype
10
2
20.0
8
80.0
31,8
14.6
5 50.0
5
50.0
HL
9651/3 Lymphocyte-rich/lymphocyte-predominant Total
9
1
11.1
8
88.9
50.7
23.6
5 55.6
4
44.4
55
17
30.9
38
69.1
36.8
19.8
31 56.4
24
43.6
To determine LSD1 expression in hematopoiesis and hematopoietic neoplasms, bone marrow trephine biopsies were decalcified and immunostained by using a monoclonal anti-mouse antibody against LSD1 (1:500; Novus Biologicals, Littleton, CO). Intensity of expression was assessed as either none or background (negative) or moderate or strong (positive). Expression was positive in myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS), normal bone marrow, and reactive bone marrow if 1 to 3 lineages showed intensive expression, which was most often observed in the erythroid and megakaryocytic lineage. In acute leukemias, blasts only were scored. To determine LSD1 expression in lymphoid neoplasms, tissue microarrays of lymphoid tissues were immunostained with anti-mouse antibody against LSD1 (1:2000; Novus Biologicals). Samples with expression in less than 10% of tumor cells were scored as negative; moderate or strong staining in more than 10% of tumor cells was scored positive. Tissue microarrays were constructed from lymphoma tissue samples reclassified according the World Health Organization 2008 classification and were obtained from the archives of the Institute of Pathology at the University of Bonn as described.9 LSD1 was expressed in 75 (48.4%) of 155 hematopoietic neoplasms but in only 123 (34.7%) of 354 lymphoid neoplasms (Pearson x2 test P , .004). Statistically significant differences were also found in expression of normal and reactive bone marrow (Fisher’s exact test P , .001) and normal and neoplastic bone marrow (Fisher’s exact test, P , .002). Among lymphoid neoplasms, there was a significant difference between high-grade and low-grade B-NHLs (Pearson x2 test P , .001). Expression in B-NHLs combined differed from T-cell NHLs (T-NHLs) as well as from Hodgkin lymphomas (HLs) (Pearson x2 test, P , .001 in both cases). All calculations were performed by using SPSS Statistics for Windows, Version 20 (IBM, Armonk, NY). AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; ALL, acute lymphoblastic leukemia; B-ALL, B-cell ALL; CLL, chronic lymphocytic leukemia, B-cell type; CML, chronic myelogenous leukemia; CMML, chronic myelomonocytic leukemia; DLBCL, diffuse large B-cell lymphoma; ET, essential thrombocythemia; F, female; ICD-O-03, International Classification of Diseases-Oncology, third edition; M, male; NA, not applicable; NOS, not otherwise specified; PMF, primary myelofibrosis; PTCL, peripheral T-cell-lymphoma; PV, polycythemia vera; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RARS, refractory anemia with ringed sideroblasts; SLL, small lymphocytic lymphoma; SD, standard deviation; T-ALL, T-cell ALL.
7. Kerenyi MA, Shao Z, Hsu YJ, et al. Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation. Elife. 2013;2:e00633.
9. Khristi J, Mey U, Kirfel J, Schmidt-Wolf IG, Gutgemann ¨ I. Sequential Hodgkin’s and non-Hodgkin’s lymphoma in non-immunocompromised patients. Ann Hematol. 2013;92(11):1565-1567.
8. Sprussel ¨ A, Schulte JH, Weber S, et al. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia. 2012;26(9):2039-2051.
© 2014 by The American Society of Hematology
From www.bloodjournal.org by guest on June 5, 2015. For personal use only.
2014 124: 151-152 doi:10.1182/blood-2014-04-569525
Lysine-specific demethylase 1 (LSD1) in hematopoietic and lymphoid neoplasms Dennis Niebel, Jutta Kirfel, Viktor Janzen, Tobias Höller, Michael Majores and Ines Gütgemann
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