dup (11q) in myeloid malignancies

2016-11-01   Soad Al Bahar  , Adriana Zamecnikova  

1./ Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait annaadria@yahoo.com

Abstract

Partial gain of the long arm of chromosome 11, containing the unrearranged mixed lineage leukaemia (MLL) gene (KMT2A; lysine (K)-specific methyltransferase 2A) is a rare but recurrent anomaly in myeloid malignancies, and is often associated with an older age and a higly complex karyotype.

Clinics and Pathology

Disease

Chronic myeloproliferative neoplasms and acute myeloid leukemia (AML).

Phenotype stem cell origin

Phenotype / cell stem origin 25 of the 29 cases presented were AML, 3 were diagnosed with myelodysplasia (MDS) (Werner et al., 1992; Harrison et al., 1998; MacGrogan et al., 2004) and 1 with chronic myeloid leukemia (CML) (Pedersen et al., 2000). While the most common phenotype of AML cases with MLL translocations is AML-M4/M5, the phenotype of AML cases was AML-M1 (7 patients) mainly (Soni et al., 1996; Green et al.,1999; Cuthbert et al., 2000; Brezinova et al., 2002; Mrozek et al., 2002; Arnaud et al., 2005; Babicka et al., 2007). In addition, there were 1 AML-M0 (Van Limbergen et al., 2002), 5 AML-M2 (Soni et al., 1996; Mauritzson et al., 2002; Van Limbergen et al., 2002; Rucker et al., 2006), 1 AML-M4 (Harrison et al., 1998), 4 AML-M5 (Kaneko et al., 1982; Harrison et al., 1998; Xu et al., 2001), 1 AML-M7 (Dastugue et al., 2002) and 6 AML not specified cases (Smadja et al., 1989; Lai et al., 1995; Andersen et al., 2005; Babicka et al., 2007; Lessard et al., 2007; Huh et al., 2013). Among the 29 patients, 1 patient developed AML after therapy for multiple myeloma (Soni et al., 1996), 2 after therapy for adenocarcinoma (Mauritzson et al., 2002; Andersen et al., 2005) and 1 after chemotherapy for diffuse large B-cell lymphoma (Huh et al., 2013) (Table 1).
 Sex/ AgeDiagnosisKaryotype
1F/0AML- M551,XX,+1,del(1)(p22)x2,+3,+6,+9,add(10)(p13),dup(11)(q11q21),+19/52,idem,+18
2F/60 AML44,XX,der(1)t(1;4)(q11;p11),+der(1)t(1;7)(p11;p11),-4,del(5)(q14q34),der(7)t(7;17)(q11;q11),dup(11)(q12q13),-12,-17,-20,+mar
3M/84RAEB46,XY,dup(11)(q13q25)
4M/53AML44-45,XY,-3,-5,-10,dup(11)(q12q13),add(12)(p12),add(14)(q32),der(17)t(5;17)(p11;p11),i(18)(q10), +1-2mar
5M/59AML-M149-52,XY,+1,+der(2)t(2;11)(q27;q11),der(3)t(3;3)(q23;p23),del(6)(q23),+10, del(11)(q21q23),+dup(11)(q23), +13,add(14)(p13),add(16)(p23),-17,-17,-18,der(19)t(17;19)(q21;p13),inc
6F/83AML- M244-47,XX,-5,der(6)t(6;13)(p22;q21),+der(11)ins(11;11)(q24;q?12q14),+dup(11)(q23q25),+i(11)(q10),del(13)(q?),der(16)t(13;16)(q?;q?13),del(17)(p?),-18, der(22)t(13;22)(q?;p11)
multiple myeloma, chemotherapy
7M/45 AML-M5a46,XX,dup(11)(q23q23)
8F/15AML-M449,XX,+8,+8,+8,dup(11)(q14q23)/50,idem,+mar
9M/77AML-M5b45,XY,-10,dup(11)(q23q24)
10M/63RA43,X,-Y,del(5)(q13q33),der(7)t(7;13)(p22;q1?),-9,der(11)add(11)(p15)dup(11)(q14q23),-13
11 M AML-M1 43,XY,del(5)(q15q33),-7,-11,dup(11)(q13q23),-17,der(18)t(7;18)(q22;q23)/44, idem,+mar
12F/76 AML-M1 45,XX,del(5)(q13q33),del(7)(q?11q36),dup(11)(q23q23),-16,add(16),der(18)t(16;18)(?;p11)
13F/66CML45,XX,-7,-9,t(9;22),add(10)(q26),dup(11)(q22q23),der(19),+del(22)(q?)
14M/23APL/ AML-M5a46,XY,dup(11)(q?),t(15;17)(q22;q21)
15F/66AML-M146,XX,del(5)(q13q33),dup(11)(q13q23),t(17;20)(q12;q11)/46,XX,del(5),del(7)(q21q31),+8,dup(11)(q23q23), -14,der(17)t(14;17)(q21;q12),der(20)t(17;20)/46,XX,del(5),del(7),+8,der(11)t(11;11)(q23;p?),-14,der(17) t(14;17),der(20)t(17;20)
16M/1 AML-M7 DS 44,XY,t(9;15)(p11;q11),dup(11)(q11q13),-13,-15,-16,der(17)t(16;17)(q11;p11),+21c, der(21)t(13;21)(q21;p11)
17F/61MDS AML-M246,XX,t(6;9)(p11;p11),t(6;13)(p25;q14),ins(17;1)(q25;q21q25),del(19)(q12)/47,idem,+21
46,XX,t(6;9),t(6;13),-13,+mar/46,XX,del(1)(p11p32),-4,-5,add(7)(q31-32),-9, +dup(11)(q13q23),-12,del(14) (q22),-16,-17,ins(17;1),+der(?)t(?;12)(?;q?), +2mar
adenocarcinoma, chemotherapy, radiotherapy
18M/80AML-M144,X,-Y,del(5)(q13q33),der(5)t(5;11)(q35;q13),-7,der(21)t(7;21)(?;q2?1)t(7;21)t(7;21)t(7;21) t(7;21)t(7;21)/ 44,X,-Y,del(5),-7,der(16)t(11;16)(q13;q24),der(21)/44,X,-Y,del(5),-7,dup(11)(q23q25),der(21)
19F/68AML- M243,XX,-4,del(5)(q12q34),der(10)t(1;10)(p13;q26),dup(11)(q?24q?),-17,-18
20M/63AML-M045,XY,der(2)t(2;18)(p13;p11),del(5)(q13q33),der(7)t(7;11),der(11;12)(q10;q10),dup(11)(q?24q?),+13,der(13)t(7;13)(q?;q21)x2,-16,der(17)t(2;17) (p13;q21),der(17)t(7;17)(?;q24), der(18)t(18;20)(q?;p11),der(20)t(7;20)
21M/76AML- M246,XY,der(1;19)t(1;19)(p13;p12)t(1;19)(p36;q13),der(5)t(5;17)(q13;q11-22), dup(11)(q?24q?),der(17)r(5;17) -19,+22,i(22)(q10)x2
22MRAEB44-49,XY,+Y,del(1)(q32),add(2)(p25),del(5)(q15q31),der(6)t(2;6)(q21;q13),del(7)(q22),+9,add(9)(q34)x2, add(11(p13),dup(11)(q13q23),-17,add(17)(p11), add(19)(p13),-20,i(21)(q10),+2mar
23F/86AML 44,XX,dic(5;17)(q11;p11),-7,der(10)t(10;11)(q25;q22)/43,idem,del(3)(p21),dic(4;7)(q11;q11),+7,der(8)t(4;8) (q21;p21),-12,der(12)t(12;21)(p13;q22),der(21)t(12;21)(q?;q21)/43,idem,del(3),dic(4;7),+7,der(8)(4;8),dup(11)(q23q23),-12,der(12)t(12;21),der(21)t(12;21)
adenocarcinoma, chemotherapy
24F/60AML-M146,XX,der(3)t(3;11)(q29;q11)/46,XX,dup(11)(q14q23)
25F/64AML-M244,XX,del(2)(q31q35),-4,del(5)(q13q33),-11,dup(11)(q21q23),-14,del(17)(q21),del(18)(q21),+mar
26M/62 AML 45,XY,del(5)(q13q33),del(7)(q22q35),dup(11)(q?),der(17)t(17;21)(p11;?),der(20)t(20;21)(q12;?),-21/ 44,XY, del(4)(q32),del(5),der(7)t(3;7)(q?;q21),-15,der(16)t(15;16)(?;q22),der(17)t(17;21),der(20)t(20;21),-21
27F/66AML-M146,XX,del(5)(q13q33),del(7)(q21q33),dup(11)(q13q23),-17,der(20)t(17;20)(q12;q11)/46,XX,del(5), del(7),+8, dup(11),-14,der(17)t(14;17)(?;q12),der (20)t(17;20)
28M/60AML46,XY,del(5)(q13q33),dup(11)(q23q23)/43,idem,-4,-17,-18/42,idem,del(2)(q21),-6,-dup(11), add(12)(p11), del(12)(p11),-16,-17,-18
29M/63AML42,X,-Y,del(1)(q32),add(2)(q13),-4,add(4)(q31),del(5)(q15q33), add(6)(p25), add(6)(q13),der(7;16)(p10;q10), -8,add(10)(p13),dup(11)(q23q25),add(13)(p11),-16,-17,add(18)(q12),add(20)(q13),+2mar
diffuse large B-cell lymphoma, chemotherapy

Abbreviations: F., female; M., male; AML., acute myeloid leukemia; AML-M5., acute monoblastic leukemia; RAEB., refractory anemia with excess of blasts; AML-M1., acute myeloblastic leukemia without maturation; AML-M2., acute myeloblastic leukemia with maturation; AML-M5a., acute monoblastic leukemia without differentiation; AML-M4., acute myelomonocytic leukemia; AML-M5b., acute monocytic leukemia; RA., refractory anemia; CML., chronic myeloid leukemia; APL., acute promyelocytic leukemia; DS., Downs syndrome; MDS., myelodysplastic syndrome; AML-M0., acute myeloblastic leukemia with minimal differentiation.

.

Kaneko et al., 1982; 2. Smadja et al., 1989; 3. Werner et al., 1992; 4. Lai et al., 1995; 5-6. Soni et al., 1996; 7-10. Harrison et al., 1998; 11. Green et al.,1999; 12. Cuthbert et al., 2000; 13. Pedersen et al., 2000; 14. Xu et al., 2001; 15. Brezinova et al., 2002; 16. Dastugue et al., 2002; 17. Mauritzson et al., 2002; 18. Mrozek et al., 2002; 19-21. Van Limbergen et al., 2002; 22. MacGrogan et al., 2004; 23. Andersen et al., 2005; 24. Arnaud et al., 2005; 25. Rucker et al., 2006; 26-27. Babicka et al., 2007; 28. Lessard et al., 2007; 29. Huh et al., 2013.

Prognosis

The over-representation of complex karyotypes in association with unbalanced rearrangements and/or chromosome 5 and 7 anomalies may reflect genomic instability and correlate with an unfavorable outcome in patients with 11q duplications.

Epidemiology

16 male and 13 female patients with median age of 63 years (range 0 to 86 years), among them 2 were infants (aged 0 and 1 years) and a single pediatric case aged 15 years. The ages of the adult patients ranged from 23 to 86 years, with a mean age of 63 years.

Cytogenetics

Note

Fluorescence in situ hybridisation (FISH) allows identification of genes included in the amplified regions such as duplicated copies of MLL located together on the same chromosome arm without gene splitting.

Cytogenetics morphological

Identified as add(11)(q) with cytogenetically heterogeneous breakpoints by conventional cytogenetic analysis. The involved region was within the 11q13 to 25 bands in the majority of patients, clustering within the 11q13 to 23 and 11q23 to 25 regions and within the 11q11 to 21 bands in 4 cases.

Additional anomalies

Significantly associated with complex karyotypes; sole anomaly only in 2 patients:1 with refractory anemia with excess of blasts (Werner et al., 1992) and 1 AML case (Harrison et al., 1998), associated with monosomy 10 in 1 (Harrison et al., 1998,), pentasomy 8 in 1 (Harrison et al., 1998) and found in an unrelated clone in 1 AML case (Harrison et al., 1998). Highly complex anomalies in the remaing cases including dicentric chromosomes, highly rearranged chromosome derivatives and unbalanced structural aberrations; loss or deletion of chromosome 5 was found in 10 patients (Smadja et al., 1989; Lai et al., 1995; Soni et al., 1996; Harrison et al., 1998; Mauritzson et al., 2002; Van Limbergen et al., 2002; Van Limbergen et al., 2002; Rucker et al., 2006; Lessard et al., 2007; Huh et al., 2013), while simultaneous loss or deletion of chromosomes 5 and 7 was found in 7 (Green et al.,1999; Cuthbert et al., 2000; Brezinova et al., 2002; Mrozek et al., 2002; MacGrogan et al., 2004; Babicka et al., 2007; Babicka et al., 2007).Loss or deletion of chromosomes 5 and 7 was accompanied with -17 or 17p rearrangements in 11 cases (Smadja et al., 1989; Lai et al., 1995; Soni et al., 1996; Green et al.,1999; Mauritzson et al., 2002; Van Limbergen et al., 2002; MacGrogan et al., 2004; Babicka et al., 2007; Babicka et al., 2007; Lessard et al., 2007; Huh et al., 2013).

Result of the Chromosomal Anomaly

Oncogenesis

The MLL gene, located at 11q23, is frequently rearranged in acute leukaemia as either gene fusions or partial tandem duplications, but 11q duplication is a relatively rare anomaly in myeloid malignancies. In the majority of cases it is found as a part of a highly complex karyotype representing clonal evolution that plays a role in disease progression. Chromosome dupplications occurs in a broad spectrum of malignancies and typically leads to inappropriate activation or overexpression of one or more oncogenes located within the amplicon. FISH and expression analyses confirmed MLL as a prominent target within 11q23 copy gain or amplification, providing further evidence for an etiologic role for MLL gain of function in myeloid malignancies. However, as varying and often large parts of 11q are involved in chromosome duplication, it is possibile that gains of other genes such as DDX6, ETS1, and FLI1 may contribute to leukemogenesis as a gain-of-function mutation (Pope et al., 2004).

Article Bibliography

Pubmed IDLast YearTitleAuthors
156454892005Centromeric breakage and highly rearranged chromosome derivatives associated with mutations of TP53 are common in therapy-related MDS and AML after therapy with alkylating agents: an M-FISH study.Andersen MK et al
161025802005Screening by fluorescence in situ hybridization for MLL status at diagnosis in 239 unselected patients with acute myeloblastic leukemia.Arnaud B et al
166871732007Analysis of complex chromosomal rearrangements in adult patients with MDS and AML by multicolor FISH.Babicka L et al
124819042002Variations in MLL amplification in a patient with acute myeloid leukemia.Brezinová J et al
110690232000MLL amplification in acute leukaemia: a United Kingdom Cancer Cytogenetics Group (UKCCG) study.Cuthbert G et al
120913562002Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Français de Cytogénétique Hématologique (GFCH).Dastugue N et al
106024161999Lack of IRF-1 expression in acute promyelocytic leukemia and in a subset of acute myeloid leukemias with del(5)(q31).Green WB et al
95932861998Ten novel 11q23 chromosomal partner sites. European 11q23 Workshop participants.Harrison CJ et al
234837872013Therapy-related myeloid neoplasms in 39 Korean patients: a single institution experience.Huh HJ et al
69539841982Chromosome pattern in childhood acute nonlymphocytic leukemia (ANLL).Kaneko Y et al
78850351995Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a high incidence of P53 mutations.Lai JL et al
175749592007Fluorescence in situ hybridization analysis of 110 hematopoietic disorders with chromosome 5 abnormalities: do de novo and therapy-related myelodysplastic syndrome-acute myeloid leukemia actually differ?Lessard M et al
153345432004Structural integrity and expression of the L3MBTL gene in normal and malignant hematopoietic cells.MacGrogan D et al
124547412002Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001.Mauritzson N et al
119795482002Spectral karyotyping in patients with acute myeloid leukemia and a complex karyotype shows hidden aberrations, including recurrent overrepresentation of 21q, 11q, and 22q.Mrózek K et al
108618102000Many unbalanced translocations show duplication of a translocation participant. Clinical and cytogenetic implications in myeloid hematologic malignancies.Pedersen B et al
129469922004Expression analyses identify MLL as a prominent target of 11q23 amplification and support an etiologic role for MLL gain of function in myeloid malignancies.Poppe B et al
168648562006Disclosure of candidate genes in acute myeloid leukemia with complex karyotypes using microarray-based molecular characterization.Rücker FG et al
27907471989Refractory anemia with excess of blasts in transformation. Clinical, hematologic, and cytogenetic findings in nine patients.Smadja N et al
86184371996Clinical and morphological features of cases of trisomy 13 in acute non-lymphocytic leukemia.Soni M et al
117469882002Identification of cytogenetic subclasses and recurring chromosomal aberrations in AML and MDS with complex karyotypes using M-FISH.Van Limbergen H et al
16362491992Chromosome analyses in patients with myelodysplastic syndromes: correlation with bone marrow histopathology and prognostic significance.Werner M et al
115160962001Molecular cytogenetic characterization and clinical relevance of additional, complex and/or variant chromosome abnormalities in acute promyelocytic leukemia.Xu L et al

Summary

Note

A different mode of duplication is the internal partial tandem duplication (PTD) of KMT2A (MLL) (MLL-PTD), repeating the 5 part of the gene leading to its self-fusion. MLL-PTD occurs in approximately 10% of cytogenetically normal acute myeloid leukemias (AML) and in the majority of AML cases with trisomy 11 as a sole abnormality.
Atlas Image
(A) Partial karyotypes with 11q duplication. (B) Fluorescence in situ hybridization (FISH) with LSI MLL (Vysis/Abott, USA) showing intrachromosomal duplication of MLL (KMT2A) (2 fusion signals on 11q+) on metaphase and interphase cells.

Citation

Soad Al Bahar ; Adriana Zamecnikova

dup (11q) in myeloid malignancies

Atlas Genet Cytogenet Oncol Haematol. 2016-11-01

Online version: http://atlasgeneticsoncology.org/haematological/1629/tumors-explorer/favicon/haematological-explorer/