Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

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

Written2018-06Lubomir Mitev, Lilya Grahlyova, Aselina Asenova
Military Medical Academy, Department of Cytogenetics and Molecular Biology, Sofia, Bulgaria,

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

Keywords Chromosome 14; Chromosome 16; IGH; MAF; Multiple myeloma; Plasma cell leukemia

(Note : for Links provided by Atlas : click)


ICD-Topo C420,C421,C424
ICD-Morpho 9732/3 Plasma cell myeloma / Multiple myeloma
ICD-Morpho 9733/3
Atlas_Id 1308
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.

Clinics and Pathology

Disease Multiple myeloma (MM)
Phenotype / cell stem 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).


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 NameIGH
Location 14q32.33
Gene NameMAF
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.


MAF (v-maf musculoaponeurotic fibrosarcoma oncogene homolog (avian))
Eychöne, A ; Pouponnot, C
Atlas Genet Cytogenet Oncol Haematol. 2010;14(9):822-826.
Mgr. Mi?ková Pavla; Mgr. Balcárková Jana, Ph.D.; MUDr. PikaTom ;RNDr. Holzerová Milena, Ph.D.; Nevimová Klára; Prof.MUDr. ?udla Vlastimil, CSc.; prof. MUDr. Indrák Karel , DrSc.; Prof. RNDr. Mgr. Jaroöová Marie, CSc.
2013 18th Congress of the European Hematology Association
PMID B1482
Chromosome aberrations in a series of 120 multiple myeloma cases with abnormal karyotypes
Mohamed AN, Bentley G, Bonnett ML, Zonder J, Al-Katib A.
Am J Hematol. 2007 Dec;82(12):1080-7
PMID 17654686
A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression
Annunziata CM1, Hernandez L, Davis RE, Zingone A, Lamy L, Lam LT, Hurt EM, Shaffer AL, Kuehl WM, Staudt LM
Blood. 2011 Feb 24;117(8):2396-404. doi: 10.1182/blood-2010-04-278788. Epub 2010 Dec 16
PMID 21163924
The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms
Arcaini L, Zibellini S, Boveri E, Riboni R, Rattotti S, Varettoni M, Guerrera ML, Lucioni M, Tenore A, Merli M, Rizzi S, Morello L, Cavalloni C, Da Vià MC, Paulli M, Cazzola M
Blood. 2012 Jan 5;119(1):188-91. doi: 10.1182/blood-2011-08-368209. Epub 2011 Nov 9
PMID 22072557
Translocation t(14;16) and multiple myeloma: is it really an independent prognostic factor?
Avet-Loiseau H, Malard F, Campion L, Magrangeas F, Sebban C, Lioure B, Decaux O, Lamy T, Legros L, Fuzibet JG, Michallet M, Corront B, Lenain P, Hulin C, Mathiot C, Attal M, Facon T, Harousseau JL, Minvielle S, Moreau P; Intergroupe Francophone du Myélome
Blood. 2011 Feb 10;117(6):2009-11. doi: 10.1182/blood-2010-07-295105. Epub 2010 Oct 20
PMID 20962323
Chromosome translocations in multiple myeloma
Bergsagel PL, Kuehl WM
Oncogene. 2001 Sep 10;20(40):5611-22
PMID 11607813
The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages
Cao S, Liu J, Song L, Ma X
J Immunol. 2005 Mar 15;174(6):3484-92
PMID 15749884
International Myeloma Working Group molecular classification of multiple myeloma: spotlight review
Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK, Morgan G, Van Ness B, Chesi M, Minvielle S, Neri A, Barlogie B, Kuehl WM,Liebisch P, Davies F, Chen-Kiang S, Durie BG, Carrasco R, Sezer O, Reiman T, Pilarski L, Avet-Loiseau H; International Myeloma Working Group
Leukemia. 2009 Dec;23(12):2210-21. doi: 10.1038/leu.2009.174. Epub 2009 Oct 1
PMID 19798094
Secondary genomic rearrangements involving immunoglobulin or MYC loci show similar prevalences in hyperdiploid and nonhyperdiploid myeloma tumors.
Gabrea A, Martelli ML, Qi Y, Roschke A, Barlogie B, Shaughnessy JD Jr, Sawyer JR, Kuehl WM
Genes Chromosomes Cancer. 2008 Jul;47(7):573-90
PMID 18381641
Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma
Hurt EM, Wiestner A, Rosenwald A, Shaffer AL, Campo E, Grogan T, Bergsagel PL, Kuehl WM, Staudt LM
Cancer Cell. 2004 Feb;5(2):191-9
PMID 14998494
Observation on frequency & clinico-pathological significance of various cytogenetic risk groups in multiple myeloma: an experience from India
Kadam Amare PS, Jain H, Nikalje S, Sengar M, Menon H, Inamdar N, Subramanian PG, Gujral S, Shet T, Epari S, Nair R
Indian J Med Res. 2016 Oct;144(4):536-543. doi: 10.4103/0971-5916.200890.
PMID 28256461
The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines
Kim JI1, Ho IC, Grusby MJ, Glimcher LH
Immunity. 1999 Jun;10(6):745-5
PMID 10403649
Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression
Kuroda S, Yamazaki M, Abe M, Sakimura K, Takayanagi H, Iwai Y
Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14885-9. doi: 10.1073/pnas.1105133108. Epub 2011 Aug 22
PMID 21873234
Novel evidence of a role for chromosome 1 pericentric heterochromatin in the pathogenesis of B-cell lymphoma and multiple myeloma
Le Baccon P, Leroux D, Dascalescu C, Duley S, Marais D, Esmenjaud E, Sotto JJ, Callanan M
Genes Chromosomes Cancer. 2001 Nov;32(3):250-64.
PMID 11579465
Cytogenetic and fluorescence in situ hybridization studies in 60 patients with multiple myeloma and plasma cell leukemia
Lloveras E, Granada I, Zamora L, Espinet B, Florensa L, Besses C, Xandri M, Pérez-Vila ME, Millà F, Woessner S, Solé F
Cancer Genet Cytogenet. 2004 Jan 1;148(1):71-6.
PMID 14697644
Differential 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, Harizanova J, Righolt CH, Zhu G, Mai S, Belch AR, Pilarski LM
Genes Chromosomes Cancer. 2013 Jun;52(6):523-37. doi: 10.1002/gcc.22049. Epub 2013 Mar 5
PMID 23460268
Superior 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, van Rhee F, Shaughnessy JD Jr, Anaissie E, Szymonifka J, Hoering A, Alsayed Y, Waheed S, Crowley J, Barlogie B
Blood. 2010 May 27;115(21):4168-73. doi: 10.1182/blood-2009-11-255620. Epub 2010 Feb 2
PMID 20124509
Characterization of c-Maf Transcription Factor in Normal and Neoplastic Hematolymphoid Tissue and Its Relevance in Plasma Cell Neoplasia
Natkunam Y, Tedoldi S, Paterson JC, Zhao S, Rodriguez-Justo M, Beck AH, Siebert R, Mason DY, Marafioti T
Am J Clin Pathol. 2009 Sep;132(3):361-71. doi: 10.1309/AJCPEAGDKLWDMB1O
PMID 19687312
Pavlistova Lenka, Berkova Adela, Zemanova Zuzana, Svobodova Karla, Izakova Silvia, Ransdorfova Sarka, Spicka Ivan, Straub Jan, Michalova Kyra
Abstract release date: May 18, 2017) EHA Learning Center. Pavlistova L. May 18, 2017; 182650
Vascular 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, Tai YT, Lin BK, Narsimhan RP, Sattler M, Kijima T, Salgia R, Gupta D, Chauhan D, Anderson KC
J Biol Chem. 2002 Mar 8;277(10):7875-81. Epub 2001 Dec 20
PMID 11751905
MAF protein mediates innate resistance to proteasome inhibition therapy in multiple myeloma
Qiang YW, Ye S, Chen Y, Buros AF, Edmonson R, van Rhee F, Barlogie B, Epstein J, Morgan GJ, Davies FE
Blood. 2016 Dec 22;128(25):2919-2930. doi: 10.1182/blood-2016-03-706077. Epub 2016 Oct 28
PMID 27793878
Genomic profiling of myeloma: the best approach, a comparison of cytogenetics, FISH and array-CGH of 112 myeloma cases
Rack K, Vidrequin S1, Dargent JL
J Clin Pathol. 2016 Jan;69(1):82-6. doi: 10.1136/jclinpath-2015-203054. Epub 2015 Sep 3
PMID 26338801
Identification of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping
Sawyer JR, Lukacs JL, Munshi N, Desikan KR, Singhal S, Mehta J, Siegel D, Shaughnessy J, Barlogie B.
Blood. 1998 Dec 1;92(11):4269-78.
PMID 9834233
Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease
Sawyer JR, Tian E, Heuck CJ, Epstein J, Johann DJ, Swanson CM, Lukacs JL, Johnson M, Binz R, Boast A, Sammartino G, Usmani S, Zangari M, Waheed S, van Rhee F, Barlogie B.
Blood. 2014 Apr 17;123(16):2504-12. doi: 10.1182/blood-2013-12-546077. Epub 2014 Feb 4
PMID 24497533
Further cytogenetic characterization of multiple myeloma confirms that 14q32 translocations are a very rare event in hyperdiploid cases
Smadja NV, Leroux D, Soulier J, Dumont S, Arnould C, Taviaux S, Taillemite JL, Bastard C
Genes Chromosomes Cancer. 2003 Nov;38(3):234-9
PMID 14506697
New recurrent chromosome alterations in patients with multiple myeloma and plasma cell leukemia
Stella F, Pedrazzini E, Rodrèguez A, Baialardo E, Kusminsky G, Arbelbide J, Fantl DB, Slavutsky I
Cytogenet Genome Res. 2011;134(4):249-59. doi: 10.1159/000329479. Epub 2011 Jul 5
PMID 21734361
t(14;16)-positive multiple myeloma shows negativity for CD56 expression and unfavorable outcome even in the era of novel drugs
T Narita, A Inagaki, T Kobayashi, Y Kuroda, T Fukushima, M Nezu, S Fuchida, H Sakai, N Sekiguchi,I Sugiura, Y Maeda, H Takamatsu,N Tsukamoto,D Maruyama Y Kubota, M Kojima, K Sunami, T Ono, M Ri, K Tobinai, and S Iida,
Blood Cancer J. 2015 Feb; 5(2): e285.
PMID 25723856
Batf controls the global regulators of class switch recombination in both B and T cells
Wataru Ise, Masako Kohyama, Barbara U. Schraml, Tingting Zhang, Bjoern Schwer, Uttiya Basu, Frederick W. Alt, Jun Tang, Eugene M. Oltz, Theresa L. Murphy, and Kenneth M. Murphy
Nat Immunol. 2011 Jun; 12(6): 536-543.
PMID 21572431
Molecular signaling in multiple myeloma: association of RAS/RAF mutations and MEK/ERK pathway activation
Xu J, Pfarr N, Endris V, Mai EK, Md Hanafiah NH, Lehners N, Penzel R, Weichert W, Ho AD, Schirmacher P, Goldschmidt H, Andrulis M,Raab MS
Oncogenesis. 2017 May 15;6(5):e337. doi: 10.1038/oncsis.2017.36
PMID 28504689


This paper should be referenced as such :
Lubomir Mitev, Lilya Grahlyova, Aselina Asenova
t(14;16)(q32;q23) IGH/MAF
Atlas Genet Cytogenet Oncol Haematol. 2019;23(5):129-132.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes CD38 MAF

Translocations implicated (Data extracted from papers in the Atlas)

 t(14;16)(q32;q23) IGH/MAF

External links

Mitelman databaset(14;16)(q32;q23)
arrayMap (UZH-SIB Zurich)Morph ( 9732/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9733/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Oct 8 16:37:26 CEST 2021

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us