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Prepublished online as a Blood First Edition Paper on October 3, 2002; DOI 10.1182/blood-2002-08-2436.
NEOPLASIA
From the Laboratory of Hematology, University Hospital,
and Department of Clinical Hematology, University Hospital, Nantes,
France.
In an attempt to address the issue of cytogenetic features of
multiple myeloma (MM) variants, we have analyzed a series of 8 IgM, 9 IgD, 2 IgE, and 14 nonsecretory (NS) MM cases using fluorescence in
situ hybridization. A very high incidence (83%) of t(11;14)(q13;q32) was detected in the IgM (7 of 8), IgE (2 of 2), and NS (11 of 14) MM
cases, but not in the IgD cases (2 of 9). Of note, no t(4;14) was
observed in this cohort of patients. This increased incidence of
t(11;14) was associated with 2 dominant features in these variants, namely, a "lymphoplasmacytic" presentation mainly in IgM MM and a
lower secreting capacity in the others, 2 features previously associated with t(11;14). Of major interest, t(11;14) was never observed in Waldenström macroglobulinemia or in IgG/IgA
"lymphoplasmacytic" lymphomas. Thus, for unknown
reasons, t(11;14) is the hallmark of IgM, IgE, and NS MM, (but not IgD
MM), with a 5-fold increase of its incidence compared to that of IgG
and IgA MM.
(Blood. 2003;101:1570-1571) Most multiple myelomas (MMs) and primary
plasma cell leukemias (PCLs) are characterized by the secretion of a
monoclonal component, mainly of IgG and IgA types, and less frequently
of Bence Jones, that is, light-chains only type. However, in rare cases
of MM/primary PCL, other monoclonal components are found in the serum
of patients, that is, IgD (1%-2% of the cases), IgM (0.2% of the
cases), or IgE (even less frequent).1 Finally, some
patients are characterized by the absence of any detectable monoclonal
component, either in the serum or in the urine, and are described as
having nonsecretory (NS) MM. To further characterize these MM variants,
we have analyzed the chromosomal abnormalities of 8 patients with IgM
MM, 9 patients with IgD MM, 2 patients with IgE MM, and 14 patients
with NS MM. We report a very high incidence (83%) of t(11;14) in IgM,
IgE, and NS MM, but not in IgD MM, in which t(11;14) has the same
incidence as that of IgG and IgA MM (16%).2
Patients with variant isotypes
Control population
FISH experiments All the MM samples have been purified using the Miltenyi technology (anti-CD138-coated magnetic beads; Paris, France), as previously reported.2 After purification, plasma cells were fixed, and fluorescence in situ hybridization (FISH) experiments, using probes specific for the chromosome 14q32 rearrangements, that is, t(14q32) and the t(4;14) and t(11;14) translocations were performed. The technique and the probes have been previously published.3
A high incidence of t(11;14) was observed in IgM, IgE, and NS MM,
but not in IgD MM. Indeed, whereas t(11;14) is
observed in 16% of all MM and in 2 of 9 (22%) IgD MM cases, FISH
analysis of IgM MM revealed IGH-CCND1 fusion(s) in 7 of 8 cases (88%; Table 1). A similar high incidence was observed in IgE
MM (2 of 2) and in NS MM (11 of 14; 79%). Overall, t(11;14) was
observed in 83% of IgM, IgE, and NS MM cases, a 5-fold increase as
compared to IgD and IgG/IgA MM. Of note, none of these patients
presented t(4;14): 0 of 33 versus 66 of 679 (10%;
P = .14). Thus, IgM, IgE, and NS MM present a strikingly
higher incidence of t(11;14) than IgD or other classical MM, all these
variants lacking t(4;14). A literature survey did not reveal any
cytogenetic analysis in variant MM cases, but showed a cryptic t(11;14)
in the unique IgE myeloma cell line.7 In the control MM
population, ie, IgG, IgA, and light-chains only MM, the incidence of
IGH-CCND1 fusions was 15%, 10%, and 31%, respectively.
Even though light-chains only MMs differ from IgG and IgA MMs by a
higher incidence of t(11;14), this incidence is incomparable to
that observed in the current MM variants.
A "lymphoplasmacytic" morphology and a lower secreting capacity have been recently reported as the only correlations between presenting features and t(11;14) in a large cohort of individuals with MM.8 It was of interest to see if such correlations were observed in our current study. As previously emphasized,3,4 all IgM MMs had a "lymphoplasmacytic" presentation. No slide was available for the 2 IgE MM cases. Bone marrow smears of 8 of the 14 patients with NS MM were available. Interestingly, a "lymphoplasmacytic" morphology was observed in 4 of 8 cases, and especially in 4 of 6 of the t(11;14)+ cases. Thus, a "lymphoplasmacytic" morphology is the hallmark of IgM and NS MM at least, but not of IgD MM. Of note, whereas in LPL and WM, malignant cells are essentially lymphoid cells with a plasmacytic inflection, in MM variants, the cells resemble essentially small mature plasma cells, rather than "lymphoplasmacytic" cells, and correspond to the "small cell type" of the Bartl classification.9 Finally, the analysis of 16 LPL and 13 WM cases failed to identify any IGH- CCND1 fusion. What about the correlation with a lower secreting capacity? Fourteen of these 22 variants were NS MMs, thus directly involved in this correlation. On the other hand, in comparison with classical IgG and IgA MMs, IgM cases were not low-secretory MMs (median serum M component = 64 g/L; range = 14-95 g/L). NS MM presents a special form of sterile plasma cells, characterized by an incapacity to assemble Ig chains.10 However, from an immunologic viewpoint, they have to be considered as postswitch MM. Of note, an abnormally high (but to a much lesser extent) incidence of t(11;14) is also observed in light-chains only MM.3 A likely hypothesis would be to consider that this MM subclass would be heterogeneous, some of them corresponding to NS (or low-secreting) MM. Careful prospective analyses of light-chains only MM would enable us to answer this question. Interestingly, a high incidence (55%) of t(11;14) has also been reported in systemic amyloidosis, another form of plasma cell dyscrasia characterized by a low but amyloidogenic light-chain production.11 Overall, a plausible hypothesis would be to consider that t(11;14) is mainly observed in clones with small mature cell type or low-secreting features or both. Until now, the reasons for the specific selection of the 11q13 chromosomal region in the MM variants remain unknown, as it remains unknown in mantle cell lymphoma (MCL), the only B-cell malignancy with 100% of such translocations. Furthermore, the molecular consequences of the up-regulation of the cyclin D1 are totally obscure because patients with t(11;14) do not display a higher proliferative index (personal data and Fonseca et al8) and have a better prognosis.12 This is compatible with the well-documented better prognosis of NS MM,13 knowing that the prognosis of IgM and IgE MM is not evaluable (not > 0.2% of the cases). Further experiments, especially using the microarray technology, should enable us to decrypt the molecular changes associated with this specific translocation.
We thank all the physicians who referred the specimens to us: Dr Azais (Poitiers), Dr Boiron (Bordeaux), Pr Lassoued (Amiens), Dr Lelouche (Quimper), Dr Maisonneuve (La Roche/Yon), Dr Delbrel (Bordeaux), Dr Sadoun (Poitiers), and Dr Vuillier (Besancon).
Submitted August 9, 2002; accepted September 18, 2002.
Prepublished online as Blood First Edition Paper, October 3, 2002; DOI 10.1182/blood- 2002-08-2436.
Supported by the Association pour la Recherche sur le Cancer and a Programme Hospitalier de Recherche Clinique.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Hervé Avet-Loiseau, Laboratoire d'Hématologie, Institut de Biologie, 9 quai Moncousu, 44093 Nantes Cedex 1, France; e-mail: havetloiseau{at}chu-nantes.fr.
1. MacLennan ICM. In which cells does neoplastic transformation occur in myelomatosis? Curr Top Microbiol Immunol. 1992;182:209-213[Medline] [Order article via Infotrieve].
2.
Avet-Loiseau H, Facon T, Grosbois B, et al.
Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features and clinical presentation.
Blood.
2002;99:2185-2191 3. Juge-Morineau N, Heirman C, Bakkus M, et al. Immunoglobulins D and M multiple myeloma variants are heavily mutated. Clin Cancer Res. 1997;3:2501-2506[Abstract].
4.
Sahota SS, Garand R, Mahroof R, et al.
V(H) gene analysis of IgM-secreting myeloma indicates an origin from a memory cell undergoing isotype switch events.
Blood.
1999;94:1070-1076
5.
Sahota SS, Garand R, Bataille R, Smith AJ, Stevenson FK.
VH gene analysis of clonally related IgM and IgG from human lymphoplasmacytoid B-cell tumors with chronic lymphocytic leukemia features and high serum monoclonal IgG.
Blood.
1998;91:238-243 6. Garand R, Sahota SS, Avet-Loiseau H, et al. IgG-secreting lymphoplasmacytoid leukaemia: a B-cell disorder with extensively mutated VH genes undergoing Ig isotype-switching frequently associated with trisomy 12. Br J Haematol. 2000;109:71-80[CrossRef][Medline] [Order article via Infotrieve]. 7. Gabrea A, Bergsagel PL, Chesi M, Shou Y, Kuehl WM. Insertion of excised IgH switch sequences causes overexpression of cyclin D1 in a myeloma tumor cell. Mol Cell. 1999;3:119-123[Medline] [Order article via Infotrieve].
8.
Fonseca R, Blood EA, Oken MM, et al.
Myeloma and the t(11;14)(q13;q32): evidence for a biologically defined unique subset of patients.
Blood.
2002;99:3735-3341 9. Bartl R, Frisch B, Fateh-Moghadam A, Kettner G, Jaeger K, Sommerfeld W. Histologic classification and staging of multiple myeloma: a retrospective and prospective study of 674 cases. Am J Clin Pathol. 1987;87:342-355[Medline] [Order article via Infotrieve]. 10. Preud'Homme JL, Hurez D, Danon F, Brouet JC, Seligmann M. Intracytoplasmic and surface-bound immunoglobulins in "nonsecretory" and Bence-Jones myeloma. Clin Exp Immunol. 1976;25:428-436[Medline] [Order article via Infotrieve].
11.
Hayman SR, Bailey RJ, Jalal SM, et al.
Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis.
Blood.
2001;98:2266-2268
12.
Moreau P, Facon T, Leleu X, et al.
Recurrent 14q32 translocations determine the prognosis of multiple myeloma especially in patients receiving intensive chemotherapy.
Blood.
2002;100:1579-1583 13. Dreicer R, Alexanian R. Nonsecretory multiple myeloma. Am J Hematol. 1982;13:313-318[Medline] [Order article via Infotrieve].
© 2003 by The American Society of Hematology.
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  T. Bochtler, U. Hegenbart, F. W. Cremer, C. Heiss, A. Benner, D. Hose, M. Moos, J. Bila, C. R. Bartram, A. D. Ho, et al. Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability Blood, May 1, 2008; 111(9): 4700 - 4705. [Abstract] [Full Text] [PDF]
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D. Gonzalez, M. van der Burg, R. Garcia-Sanz, J. A. Fenton, A. W. Langerak, M. Gonzalez, J. J. M. van Dongen, J. F. San Miguel, and G. J. Morgan Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma Blood, November 1, 2007; 110(9): 3112 - 3121. [Abstract] [Full Text] [PDF]
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W. J. Chng, R. F. Schop, T. Price-Troska, I. Ghobrial, N. Kay, D. F. Jelinek, M. A. Gertz, A. Dispenzieri, M. Lacy, R. A. Kyle, et al. Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma Blood, October 15, 2006; 108(8): 2755 - 2763. [Abstract] [Full Text] [PDF]
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M. A. Gertz, M. Q. Lacy, A. Dispenzieri, P. R. Greipp, M. R. Litzow, K. J. Henderson, S. A. Van Wier, G. J. Ahmann, and R. Fonseca Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy Blood, October 15, 2005; 106(8): 2837 - 2840. [Abstract] [Full Text] [PDF]
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T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF]
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F. Magrangeas, M.-L. Cormier, G. Descamps, N. Gouy, L. Lode, M.-P. Mellerin, J.-L. Harousseau, R. Bataille, S. Minvielle, and H. Avet-Loiseau Light-chain only multiple myeloma is due to the absence of functional (productive) rearrangement of the IgH gene at the DNA level Blood, May 15, 2004; 103(10): 3869 - 3875. [Abstract] [Full Text] [PDF]
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Abstract
Introduction