t(14;16)(q32;q23) IGH/MAF

2018-06-01   Lubomir Mitev, MD , Lilya Grahlyova  , Aselina Asenova  

1.Military Medical Academy, Department of Cytogenetics and Molecular Biology, Sofia, Bulgaria, cytogen.vma@abv.bg

Abstract

Review on t(14;16)(q32;q23) IGH/MAF, with data on clinics, and the genes involved.

Clinics and Pathology

Disease

Multiple myeloma (MM)

Phenotype stem cell origin

t(14;16) is generated during B-cell maturation in germinal centers possibly as a result of errors in the IGH switch recombination (Bergsagel et al, 2001). The anomaly appears to be an early event in the genesis of plasma cell neoplasms (PCN) as it occurs in both MGUS and MM.

Epidemiology

t(14;16) is described in 12 cases (Mitelman database) (0.6% of all MM cases with abnormal karyotypes) (Gabrea et al, 2008; Le Baccon et al, 2001; Lioveras et al, et al, 2004; Mohamed et al, 2007; Rack et al, 2016; Sawyer et al, 1998; Sawyer et al, 2014; Smadja et al, 2003). Examinations of the large series with MM (cytogenetic diagnosis included IGH-MAF fusion probe) showed that the frequency of t(14;16) is very low - 2.2-3.2% of all MM cases (Avet-Loiseau et al, 2010; Pavlistova et al, 2017; Mickova et al, 2013). The sex ratio is M:F=1.4:1 and the anomaly has been observed only in older patients (4 cases documented: average age 62 years; range 55-72 years). The presented median age is in agreement with the data of the median patients age of the largest series with t(14;16) positive MM cases (32) reported by Avet-Loiseau et al, 2010 (63 years; range 45-75 years).

Clinics

It has been suggested that t(14;16) positive MM cases are associated with less frequent extramedullary tumor formation and negativity for CD56 expression. In the cases with t(14;16) is found also higher frequency of the IgG subtype M protein, leukocytosis, thrombocytemia, hypercalcemia and lower frequency of hypocalcemia compared with those without t(14;16) (Narita et al, 2015). The cases with t(14;16) are resistant to bortezomib therapy, because proteasome inhibitors abrogate glycogen synthase kinase 3 beta - mediated degradation of MAF protein leading to its stabilization (Qiang et al, 2016)

Cytogenetics

All reported cases presented in Mitelman database except one (with isolated t(14;16)) are with complex karyotypes. Two of them are with hyper-diploid, two with pseudo-diploid and six with hypo-diploid karyotypes. The cases with hyper-diploid karyotypes included trisomy of chromosome 3, 9, 15, 18, 19, 20 and 21 and the cases with hypo-diploid karyotypes the loss of chromosome 4, 11, 13, 16,-18, 20 and 22. All cases with complex karyotypes are associated with structural abnormalities of chromosome 1 and all except one with abnormalities of chromosome 13. Chromosome 1 anomalies are presented predominantly with unbalanced translocations including whole arm translocations with the partner chromosomes 4, 5, 8, 15, 16, 18, 19, 20 and 22. In most of the cases the breakpoint in chromosome 1 is in the region 1q10-21. Four cases have deletions of the short arm of chromosome 1 in the region 1p11-33 and in two cases additional material of unknown origin is attached to the bands 1q21 and 1p22. The abnormalities of chromosome 13 included monosomy of chromosome 13 in six cases and 13q deletions (in the region 13q12-22) in three cases. Deletions of 17p12 is found in two cases and numerical anomalies of the sex chromosomes in four cases (three cases with -Y and one with -X). The presented information of the additional anomalies are partially in agreement with the findings of the large cytogenetic series with MM carrying t(14;16). The most common additional abnormalities in these series are -13/13q-, amplification of 1q, trisomy or tetrasomy of chromosome 15 and structural (mostly deletions of the short arm in the region 8p21.3) and numerical of chromosome 8. Coincidence of both anomalies t(4;14) and t(14;16) is not observed (Avet-Loiseau et al, 2010; Kadam Amere et al, 2016; Mickova et al, 2013).

Disease

Plasma cell leukemia

Epidemiology

Two cases are reported (53 and 55 years old males) (Avet-Loiseau et al., 2001; Stella et al, 2011).

Cytogenetics

Both cases showed complex karyotypes: one with hyperdiploid and numerical anomalies ( +8, +9, +18 and -13) and the other with hypodiploid karyotype and numerical (-Y, -7, -8, -13, -14 and +21) and structural anomalies, including 1q rearrangements.

Prognosis

There is controversy about the prognostic value of t(14;16). Negative impact on prognosis has been suggested by Fonseca et al., 2003 and Nair et al, 2010. Pavlistova et al, 2017 identified that the median overall survival (OS) was shorter in comparison with the control group, but was not statistically significant. Avet-Loiseau et al, 2010 reported that by univariate analysis t(14;16) is not prognostic to age, beta2-microglobulin level, t(4;14), del(17p) and del(13q) and in multivariate analysis, the p value associated with t(14;16) is even less significant. The authors also found no difference for OS. Because of the contradictory data larger number of cases carrying t(14;16) is needed to establish the real prognostic relevance of t(14;16).

Note

The predisposing factors leading to the appearance of the myeloma associated 14q32 rearrangements including t(14;16) are still unknown. The formation of the 14q32 rearrangements requires nuclear co-localization of the IGH with the partner genes involved in the 14q32 translocations, respectively in the case of t(14;16) - nuclear co-localization of IGH with MAF. But the 3D FISH experiments provided by Martin et al, 2013 indicated that the MAF and IGH are not co-localized in the nucleus of the non-malignant B cells. In these cells MAF is located more peripherally in the nucleus while IGH occupies more central nuclear position. Obviously, in order for MAF to reach the nuclear position of IGH, large chromatin decondensation in the region of its locus is necessary to occur. The latter could be a consequence of an ectopic expression of the MAF gene. As is noted below, MAF is activated by ERK/MEK pathway probably as a result of RAS or BRAF mutations but these mutations are late event in MM. One possible activator of MAF in the stage of B-cell maturation in germinal centers could be the small MAF protein BATF. This transcription factor is responsible for the differentiation of the follicular T-helper cells controlling the expression of both BCL6 and MAF. In B-cells BATF is involved in class-switch recombination (CSR) controlling directly the expression of both activation-induced cytidine deaminase and IH-CH germline transcripts (Ise et al, 2011). It has been shown also that BATF induced high level of the T-bet expression through chromatin remodelling promoting effector differentiation and cell survival (Kuroda et al, 2011). However, one possible BATF induced activation of MAF required additional chromatin deregulation of the MAF locus (to be achieved open chromatin structure), because MAF is silent in mature B-cells. But if an ectopic MAF expression is occurred during an ineffective CSR (existence of unrepaired double-strand DNA breaks in the switch regions of IGH) would be at high risk for the appearance of t(14;16).

Genes Involved and Proteins

Gene name
IGH
Location
14q32.33
Gene name
MAF
Location
16q23.2
Note
MAF is a member of the basic leucine zipper transcription factors belonging to the AP1 superfamily that includes the JUN, FOS, ATF, CREB and MAF family. MAF encodes two protein isoforms which differ in their carboxy-terminus - MAF short and long form (have 30 extra amino-acids). As the other large Maf proteins (MAFA,-MAF, MAFB and NRL), MAF contains the b-Zip domain, as well as an additional amino-terminal transactivation domain (Eychene & Pouponnot, 2009-11). MAF gene plays a role in the embryonic lens fiber cell development and its germinal mutation is responsible for congenital cataract in humans. The MAF target genes are CCND2 (cyclin D2), ITGB7 ( integrin beta7) and CCR1 (C-C chemokin receptor 1). All three genes are up-regulated by MAF protein and have an important role in MM for the cell cycle progression (cyclin D2) and adhesion of the myeloma cells to bone marrow stroma cells (integrin beta 7 and CCR1) (Hurt et al, 2004). Additionally, in MM cases integrin beta 7 binds to CDH1 (E-cadherin) on the surface of stroma cells and increases the production of VEGFA (vascular endothelial growth factor) which resulted in enhanced bone marrow angiogenesis and autocrine and paracrine stimulation of the myeloma cells (Podar et al, 2001; 2002). MAF is expressed in many tissues including neural tissues, small intestine, skin and kidney. In the normal hematopoietic tissue MAF is expressed only in the nuclei of T helper 2 (TH2) cells, monocytes and macrophages, controlling the expression of IL4 and IL10 (interleukin 4 and 10) (Cao et al, 2005; Kim et al, 1999), while in the plasmocytes MAF mRNA is not expressed (Natkunam et al, 2009). It has been reported that MAF is up-regulated in B, T, NK-cell neoplasms, myeloma cell lines and approximately in 50% of the MM cases lacking t(14;16) translocation (Hurt et al, 2004; Natkunam et al, 2009). Based on the finding that the inhibition of the MEK-ERK pathway reduced the MAF transcription in cell lines and MM cases with MAF overexpression, Annunziata et al, 2011 proposed that the MAF up regulation in MM cases lacking t(14;16) is possibly caused by the activation of MEK-ERK signalling cascade. The latter is in agreement with the observation that MAF is overexpressed in the hairy cell leukemia (HCL) (Natkunam et al, 2009) where the causal genetic event is the BRAF-V600E mutation (Arcaini et al 2012). As in HCL in MM aberrant MEK-ERK pathway is also found. Mutations of KRAS, NRAS and BRAF are detected in up to 50% of the newly diagnosed MM patients, but it has been shown that only KRASG12D and BRAFV600E are consistently associated with ERK activation (Xu et al, 2017). It is logical to expect that in MM with these two mutations MAF will be overexpressed.

Highly cited references

Pubmed IDYearTitleCitations
98657131998High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies.24
236274522013Plasma cell enrichment enhances detection of high-risk cytogenomic abnormalities by fluorescence in situ hybridization and improves risk stratification of patients with plasma cell neoplasms.8
196873122009Characterization of c-Maf transcription factor in normal and neoplastic hematolymphoid tissue and its relevance in plasma cell neoplasia.8
177047432007Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization.8
211202052010Clinical utility of FISH analysis in addition to G-banded karyotype in hematologic malignancies and proposal of a practical approach.6
275320152016Target fluorescence in-situ hybridization (Target FISH) for plasma cell enrichment in myeloma.4
216118372012Fluorescence in situ hybridization analysis of chromosome aberrations in 60 Chinese patients with multiple myeloma.4
211562292010Correlation of cytomorphology, immunophenotyping, and interphase fluorescence in situ hybridization in 381 patients with monoclonal gammopathy of undetermined significance and 301 patients with plasma cell myeloma.4
329082552021The survival impact of CKS1B gains or amplification is dependent on the background karyotype and TP53 deletion status in patients with myeloma.2
312626672019Clinical Characteristics and Prognosis of MAF Deletion in Chinese Patients With Multiple Myeloma.2
312187842019Immunohistochemistry for identification of CCND1, NSD2, and MAF gene rearrangements in plasma cell myeloma.2
294633112018Myeloid transformation of plasma cell myeloma: molecular evidence of clonal evolution revealed by next generation sequencing.2
254357232014Amplification of 1q21 and other abnormalities in multiple myeloma patients from a tertiary hospital in singapore.2
339882372021Extramedullary multiple myeloma patient-derived orthotopic xenograft with a highly altered genome: combined molecular and therapeutic studies.1
324477822020High-risk cytogenetics in multiple myeloma: Further scrutiny of deletions within the IGH gene region enhances risk stratification.0
302952562018[Detection of the Cytogenetic Aberrations in Multiple Myeloma by Using Microrray Comparative Genomic Hybridization].0
286416402017[Application of CD138 Immunomagnetic Sorting Myeloma Cells Combined with Fluorescence in Situ Hybridization for Detecting Cytogenetic Abnormalities of Multiple Myeloma].0
265240362015[Detection of Molecular Cytogenetic Aberrations by Fluorescence in Situ Hybridization in Different Bone Marrow Samples of Multiple Myeloma].0
211763602010[Comparative study of genetic aberrations in human multiple myeloma cell lines and newly diagnosed MM by fluorescence in situ hybridization].0

Article Bibliography

Pubmed IDLast YearTitleAuthors
176546862007Chromosome aberrations in a series of 120 multiple myeloma cases with abnormal karyotypes.Mohamed AN et al
211639242011A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression.Annunziata CM et al
220725572012The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms.Arcaini L et al
209623232011Translocation t(14;16) and multiple myeloma: is it really an independent prognostic factor?Avet-Loiseau H et al
116078132001Chromosome translocations in multiple myeloma.Bergsagel PL et al
157498842005The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages.Cao S et al
197980942009International Myeloma Working Group molecular classification of multiple myeloma: spotlight review.Fonseca R et al
183816412008Secondary genomic rearrangements involving immunoglobulin or MYC loci show similar prevalences in hyperdiploid and nonhyperdiploid myeloma tumors.Gabrea A et al
149984942004Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma.Hurt EM et al
282564612016Observation on frequency & clinico-pathological significance of various cytogenetic risk groups in multiple myeloma: an experience from India.Kadam Amare PS et al
104036491999The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines.Kim JI et al
218732342011Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression.Kuroda S et al
115794652001Novel evidence of a role for chromosome 1 pericentric heterochromatin in the pathogenesis of B-cell lymphoma and multiple myeloma.Le Baccon P et al
146976442004Cytogenetic and fluorescence in situ hybridization studies in 60 patients with multiple myeloma and plasma cell leukemia.Lloveras E et al
234602682013Differential nuclear organization of translocation-prone genes in nonmalignant B cells from patients with t(14;16) as compared with t(4;14) or t(11;14) myeloma.Martin LD et al
201245092010Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance.Nair B et al
196873122009Characterization of c-Maf transcription factor in normal and neoplastic hematolymphoid tissue and its relevance in plasma cell neoplasia.Natkunam Y et al
117519052002Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with beta 1 integrin- and phosphatidylinositol 3-kinase-dependent PKC alpha activation.Podar K et al
277938782016MAF protein mediates innate resistance to proteasome inhibition therapy in multiple myeloma.Qiang YW et al
263388012016Genomic profiling of myeloma: the best approach, a comparison of cytogenetics, FISH and array-CGH of 112 myeloma cases.Rack K et al
98342331998Identification of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping.Sawyer JR et al
244975332014Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease.Sawyer JR et al
145066972003Further cytogenetic characterization of multiple myeloma confirms that 14q32 translocations are a very rare event in hyperdiploid cases.Smadja NV et al
217343612011New recurrent chromosome alterations in patients with multiple myeloma and plasma cell leukemia.Stella F et al
257238562015t(14;16)-positive multiple myeloma shows negativity for CD56 expression and unfavorable outcome even in the era of novel drugs.Narita T et al
215724312011The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells.Ise W et al
285046892017Molecular signaling in multiple myeloma: association of RAS/RAF mutations and MEK/ERK pathway activation.Xu J et al

Summary

Fusion gene

IGH/MAF

Note

t(14;16)(q32;q23) represents 14q32/IGH rearrangement and belongs to the group of IGH/MAF translocations (rearrangements of the genes from the MAF oncogene family MAF, MAFA and MAFB with the IGH locus). As the other two IGH/MAF translocations t(8;14)q24;q32) andt(14;20)(q13;32) is described only in plasma cell neoplasms (PCN). t(14;16)(q32;q23) resulted in the juxtaposition of the oncogene MAF ( located at 16q23) to the strong enhancer of the IGH gene (located at 14q32) causing its up regulation in the plasma cells. This anomaly is found in both multiple myeloma (MM) and its precursor monoclonal gammapathy of undetermined significance (MGUS) respectively in 5% (Avet-Loiseau et al, 2007; Fonseca et al, 2009) and 1-5% (Avet-Loiseau et al, 2002; Fonseca et al, 2002) of the cases with 14q32 rearrangements . The anomaly is cryptic and therefore in the routine practice is determinated by fluorescent in situ hybridization with DNA specific probes and/or by qPCR technique. It is difficult to be proved with the classical G-banding technique and because of this only a small number of cases with karyotypic description of t(14;16) have been reported.

Citation

Lubomir Mitev ; Lilya Grahlyova ; Aselina Asenova

t(14;16)(q32;q23) IGH/MAF

Atlas Genet Cytogenet Oncol Haematol. 2018-06-01

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