ORIGINAL ARTICLE

Frequency of inherited variants in the MEFV genein myelodysplastic syndrome and acute myeloid leukemia

Serkan Celik • Cagatay Oktenli • Emrah Kilicaslan • Fatih Tangi •

Ozkan Sayan • H. Onur Ozari • Osman Ipcioglu • Yavuz S. Sanisoglu •

M. Hakan Terekeci • Alev A. Erikci

Received: 20 April 2011 / Revised: 31 January 2012 / Accepted: 1 February 2012 / Published online: 18 February 2012

� The Japanese Society of Hematology 2012

Abstract We investigated the frequency of inherited

variants in the MEFV gene, which is mutated in familial

Mediterranean fever (FMF), in patients with acute myeloid

leukemia (AML) and myelodysplastic syndrome (MDS).

Eight MEFV gene variants (M694I, M694V, M680I (G/C-

A), V726A, R761H, E148Q and P369S) were analyzed in 33

MDS patients, 47 AML patients and 65 healthy controls;

none had a history or family history compatible with FMF.

We identified two homozygous (E148Q/E148Q), one com-

pound heterozygous (M694V/E148Q) and five heterozygous

inherited variants in the MEFV gene in AML patients. We

also identified nine heterozygous variants in MDS patients,

while we found 11 heterozygous variants in controls. The

mean overall frequency of inherited variants in the MEFV

gene rate was higher in MDS (v2 = 4.241; P = 0.039) and

AML (v2 = 3.870; P = 0.043) patients than in healthy

controls. In conclusion, this study reports high frequency of

inherited variants in the MEFV gene in patients with MDS

and AML. However, the hypothesis that MEFV is a cancer

susceptibility gene at this point remains speculative. Addi-

tional evidence from future studies is needed to allow a more

thorough evaluation of this hypothesis.

Keywords MEFV gene � Acute myeloid leukemia �Myelodysplastic syndrome

Introduction

Familial Mediterranean fever (FMF) is an autoinflamma-

tory disease of unknown etiology primarily found in pop-

ulations originating from the Mediterranean basin, mostly

Turks, Druze, Levantine Arabs, Armenians and Sephardic

Jews [1–3]. The gene responsible for FMF, symbolized

‘‘MEFV’’, located on chromosome 16p.13.3, was identified

by positional cloning by two independent consortia in 1997

[4, 5]. To date, more than 220 FMF-associated variants

have been described [6]. However, five of those variants

(M694V, M680I, V726A, E148Q and M694I) are respon-

sible for about 80% of the FMF cases and they are all

located in exon 10, except for E148Q variant [7]. The

MEFV gene is predominantly expressed in myeloid cells,

and its expression is upregulated during myeloid differen-

tiation [8]. This gene is responsible for encoding a protein

called pyrin (or marenostrin) [4, 5, 9]. The pyrin domain

can bind indirectly to at least two proteins important in

inflammation: pro-caspase-1 and the inhibitor of nuclear

factor-jB (NF-jB) kinase complex [10–12]. Thus, the

production of interleukin-1b (IL-1b) is inhibited and nor-

mal apoptosis is allowed. On the other hand, pyrin may be

S. Celik � E. Kilicaslan � F. Tangi � H. O. Ozari �M. H. Terekeci

Division of Internal Medicine, GATA Haydarpasa Training

Hospital, Istanbul, Turkey

C. Oktenli (&)

Department of Internal Medicine and Geriatrics,

Anadolu Medical Center, 41400 Kocaeli, Turkey

e-mail: cagatay.oktenli@anadolusaglik.org;

coktenli@yahoo.com

O. Sayan � A. A. Erikci

Division of Hematology, GATA Haydarpasa Training Hospital,

Istanbul, Turkey

O. Ipcioglu

Department of Biochemistry, GATA Haydarpasa Training

Hospital, Istanbul, Turkey

Y. S. Sanisoglu

Department of Biostatistics, Yildirim Beyazit University,

Ankara, Turkey

123

Int J Hematol (2012) 95:285–290

DOI 10.1007/s12185-012-1022-0

able to modify the NF-jB pathway and apoptosis inde-

pendently of IL-1b [13–16]. Therefore, any inherited var-

iant in the MEFV gene prevents the formation of normal

pyrin protein, and it may lead to postponed apoptosis and

inflammation due to the reduced ability of pyrin to control

NF-jB and IL-1b activation [17, 18].

Most hematological neoplasms harbor constitutive NF-

jB activation and alteration of the balance between cell

proliferation and apoptosis due to distinct factors such as

gene chromosomal translocations, amplifications or point

mutations [19]. Myelodysplastic syndrome (MDS) is a

clonal stem cell disorder characterized by ineffective

hematopoiesis leading to blood cytopenias and by a high

risk of progression to acute myeloid leukemia (AML) [20,

21]. In this way, Braun et al. [21] suggested that NF-jB is

vital for MDS blasts and that NF-jB inhibition might

constitute a strategy for the eradication of such cells.

Although none of these is specific for the diseases, acti-

vating mutations of oncogenes and inactivating mutations

of tumor suppressor genes have been identified in MDS and

AML [22–25]. The inherited variants in the MEFV gene

seem to be an interesting example for genetic alterations

that lead to activation of NF-jB, which is one of the most

important drivers of the tumor-promoting machinery. In an

experimental study, it has been shown that MEFV gene was

almost predominantly expressed in cells of the myeloid

lineage and upregulated during myeloid differentiation

[26]. Interestingly, a connection between inherited variants

in the MEFV gene and hematologic malignancies was

suggested recently in two pilot studies [27, 28], which

reported the high frequency of inherited variants in the

MEFV gene, particularly MDS and AML, and some he-

matolymphoid neoplasms. As sample size was small in

these pilot studies, we aimed to investigate the frequency

of inherited variants in the MEFV gene in patients with

MDS and AML.

Patients and methods

Thirty-three patients (19 male and 14 female) with MDS

and 47 (25 male and 22 female) with AML who were all

Turkish were included in this study. They were not

symptomatic for FMF and did not have a family history of

FMF. The 65 volunteers (40 male and 25 female) were also

recruited from our check-up center without any complaint.

They were all healthy and had no symptoms, biochemical

signs or history for either FMF or myeloid neoplasms. The

study was conducted according to the recommendations set

forth by the Declaration of Helsinki on Biomedical

Research Involving Human Subjects. Each subject gave his

informed consent to the study, which was previously

approved by our local ethical committee and institutional

review board. All patients donated 2 mL of whole blood,

collected in an EDTA tube. The eight MEFV gene variants

(M694I, M694V, M680I (G/C-A), V726A, R761H, E148Q

and P369S) were detected by Dr. Zeydanli� FMF Type I

PCR System (Ankara, Turkey) based on 50 nuclease assay

method in ABI 7500 (Applied Biosystems, Foster City,

CA, USA).

Statistical analysis

Data were analyzed with SPSS 17.0 (SPSS Inc., USA)

statistical software. Differences between the groups were

investigated with the v2 test. A P B 0.05 was evaluated as

statistically significant.

Results and discussion

The mean age of the patients with MDS, AML and healthy

controls was 70.57 ± 12.33 years (age range 21–92 years),

46.94 ± 21.45 years (age range 19–78 years) and

30.25 ± 10.62 (age range 20–45 years), respectively. The

inherited variants in the MEFV gene were found in 9

(4 female and 5 male) patients with MDS, 8 (3 female and

5 male) patients with AML and 11 (2 female and 9 male)

healthy controls (Table 5). Hematological characteristics

and identified variants in the MEFV gene in patients with

MDS are shown in Table 1, while these characteristics and

identified variants in patients with AML are given in

Table 2. In the healthy control group, we found 11 hetero-

zygous variants. M694I was not found in any of the groups,

while M680I and R761H variants were found only in MDS

patients. P369S variant was found only in a healthy control.

The mean overall frequency of inherited variants in

the MEFV gene rate was higher in MDS (v2 = 4.241;

P = 0.039) and AML (v2 = 3.870; P = 0.043) patients

than healthy controls (Tables 3, 4). Interestingly, as shown

in Table 4, a screen of AML patients for common inherited

variants in the MEFV gene identified 2 homozygous

(E148Q/E148Q) and 1 compound heterozygous (M694V/

E148Q) variants; none had own and/or family history com-

patible with FMF. It is also noteworthy that E148Q is pre-

dominant variant in patients with AML. When distribution

was compared between MDS patients and controls, the fre-

quency of the M694V (v2 = 4.023; P = 0.041) and E148Q

(v2 = 6.719; P = 0.010) variants was significantly higher in

the patient group than in the controls. The M694V variant is

commonly found in FMF patients and variants located

within these hot spots are associated with more severe phe-

notypes [29]. In the present study, the findings that this

variant was significantly higher in MDS patients than in

healthy controls and none had own and/or family history

compatible with FMF are interesting.

286 S. Celik et al.

123

Speculatively, it seems likely that pyrin presumably

participates in carcinogenesis via IL-1b and/or NF-jB

pathway activation. In addition to its proinflammatory role,

IL-1b may also play a role in all phases of malignancy,

including carcinogenesis, the production of a network of

invasiveness-promoting molecules and patterns of interac-

tions of the malignant cells with the host’s immune system

[30, 31]. On the other hand, NF-jB can affect a great

diversity of genes associated with regulation of apoptosis,

cell growth, cell proliferation, differentiation, inflammation,

Table 1 Hematological characteristics and identified variants in MEFV gene in patients with myelodysplastic syndrome (MDS) (n = 33)

Patient no. Sex Age WHO BLASTS (%) WBC (9109/L) PLTS (9109/L) Hb (g/dL) Inherited variants

in MEFV gene

1 M 68 RAEB-2 18 3,320 260 9 E148Q/?a

2 M 80 RCMD 4 3,460 129 10.9 M694V/?

3 M 21 RA 4 6,100 190 10 M680I/?

4 F 74 RAEB-1 8 5,270 66.3 10.8 E148Q/?

5 F 73 RCMD 2 8,100 187 10.4 M694V/?

6 M 85 MDS-U 2 3,310 130 10.7 R761H/?

7 F 68 RAEB-2 17 3,300 267 9.5 E148Q/?

8 F 58 RA 4 5,610 233 9.6 M694V/?

9 M 79 RAEB-1 7 3,040 118 9.2 M694V/?

F female, M male, WHO World Health Organization classification, Hb hemoglobin, WBC white blood cells, PLTS platelets, RA refractory

anemia, RCMD refractory cytopenia with multilineage dysplasia, MDS-U myelodysplastic syndrome unclassified, RAEB-1 refractory anemia

with excess blasts-1, RAEB-2 refractory anemia with excess blasts-2a ? variant indicates that the chromosome carries a mutation not determined in our study

Table 2 Hematological characteristics and identified variants in MEFV gene in patients with acute myeloid leukemia (n = 47)

Patient no. Sex Age FAB category Cytogenetic risk BLASTS (%) WBC (9109/L) PLTS (9109/L) Hb (g/dL) Inherited variants

in MEFV gene

1 M 41 AML-M1 Intermediate 90 94,800 5,930 8.3 E148Q/?a

2 M 55 AML-M4 Intermediate 90 55,800 193 9.2 M694V/E148Q

3 F 57 AML-M2 Poor 83 6,250 71,500 7.4 V726A/?

4 M 35 AML-M2 Intermediate 95 11,400 199 9.1 E148Q/E148Q

5 F 50 AML-M1 Poor 70 1,500 11,500 8.7 V726A/?

6 M 18 AML-M1 Intermediate 80 12,400 68,800 9.7 E148Q/?

7 F 50 AML-M1 Intermediate 70 7,560 24 7.7 E148Q/?

8 M 36 AML-M2 Poor 80 7,540 566 10.3 E148Q/E148Q

F female, M male, AML acute myeloid leukemia, FAB French–American–British classification, Hb hemoglobin, WBC white blood cells, PLTSplateletsa ? variant indicates that the chromosome carries a mutation not determined in our study

Table 3 The comparison of the inherited variant frequency in MEFV gene between patients with myelodysplastic syndrome and normal

controls

n Overall inherited

variant allele frequency

in MEFV gene

Heterozygote variant frequencies in MEFV gene

M694V/?a E148Q/? M680I/? V726A/? M694I/? R761H/? P369S/?

Myelodysplastic syndrome 33 0.136 0.061 0.045 0.015 0 0 0.015 0

Normal controls 65 0.084 0.038 0.015 0 0.023 0 0 0.007

v2 4.241 4.023 6.719 2.197 2.411 – 2.197 0.826

P 0.039 0.041 0.010 NS NS – NS NS

NS non-significanta ? variant indicates that the chromosome carries a mutation not determined in our study

MEFV gene in MDS and AML 287

123

angiogenesis, metastasis and neoplastic transformation [19,

32]. In this way, a deregulated NF-jB activity has been

reported in malignant cells derived from patients with MDS

and AML [33–39]. Although the activation of NF-jB is not

generally observed in patients with MDS, it has been

reported that this activation was observed in a percentage of

high-risk MDS and in blasts rather than in their normal

counterparts [21, 34]. Sanz et al. [40] suggested a significant

increase in the DNA binding activity of NFjB in bone

marrow cells from patients with MDS compared with normal

donor cells. It has also been demonstrated that tumor-asso-

ciated macrophages have aberrant NF-jB activation and this

activation in myeloid cells is associated with tumor pro-

motion [41]. Although the molecular mechanism of NF-jB

activation remains elusive, several studies have character-

ized the activation level of NF-jB in bone marrow of AML

patients and more precisely in leukemic stem cells [36, 37].

Constitutive activation of the NF-jB has been described

recently in leukemic stem cells and AML blasts [36, 38]. The

activation of NF-jB may be tumor promoting in AML cells,

because of the loss of tumor suppressor expression, a pro-

longed production of growth factors for cell proliferation,

and constitutive synthesis of cyclins and other cell cycle

regulating proteins [35, 42]. IL-1b has also been implicated

in the activation of NF-jB in AML cells, which would be

responsible for the proliferation of AML cells [42, 43].

Some limitations about the present study deserve men-

tion. First, as our hospital is a referral center, the medical

records that we obtained may have been incomplete.

Therefore, cytogenetic evolution is not available in MDS

patients and prognostic value of the MEFV gene is not one of

the main aims of the present study. Second, we have notTa

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Table 5 Hematological characteristics and identified variants in

MEFV gene in healthy controls (n = 65)

Patient no. Sex Age Inherited variants

in MEFV gene

1 M 26 M694V/?a

2 M 30 E148Q/?

3 M 27 M694V/?

4 M 21 P369S/?

5 M 33 M694V/?

6 M 41 M694V/?

7 M 25 E148Q/?

8 M 29 M694V/?

9 F 42 V726A/?

10 M 38 V726A/?

11 F 29 V726A/?

F female, M malea ? variant indicates that the chromosome carries a mutation not

determined in our study

288 S. Celik et al.

123

screened genetically the pedigrees of our patients carrying

the inherited variants in the MEFV gene. But, the family

history of relatives of these patients for FMF manifestations

was negative. Likewise, as the diagnosis of FMF remains

predominantly clinical [44], the absence of FMF symptom-

atology in our patients may exclude the possibility of the

disease overlap with MDS and AML. Third, we screened

only eight inherited variants in the MEFV gene in our

patients. Therefore, we possibly missed the presence of other

and yet recognized variants. Another limitation of our study

is the very small sample size, and a larger prospective study,

especially among patients with MDS and AML, is necessary

to confirm these findings. Finally, this is a pilot study and

provides evidence of association rather than causation.

In conclusion, the main finding of the present study is a

high frequency of inherited variants in the MEFV gene in

patients with MDS. The other findings are also interesting:

we found 2 homozygous and 1 compound heterozygous

inherited variants in AML patients and a high frequency of

strong variants for FMF disease such as M694V and M680I

variants in MDS patients. However, the hypothesis that

MEFV is a cancer susceptibility gene at this point seems

speculative. An important evaluation for this hypothesis

will be to investigate additional evidence (e.g., tumors in

genetically engineered model organisms, familial aggre-

gation and monozygotic vs. dizygotic twin concordance) in

future studies.

Conflict of interest The authors of the present study have no

interest which might be perceived as posing a conflict or bias.

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