Skip to main content
main-content

01.12.2014 | Letter to the Editor | Ausgabe 1/2014 Open Access

Journal of Hematology & Oncology 1/2014

CSF3R, SETBP1 and CALR mutations in chronic neutrophilic leukemia

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2014
Autoren:
Yajuan Cui, Bing Li, Robert Peter Gale, Qian Jiang, Zefeng Xu, Tiejun Qin, Peihong Zhang, Yue Zhang, Zhijian Xiao
Wichtige Hinweise

Competing interests

RPG acknowledges support from the NIHR Biomedical Research Centre funding scheme and is a part-time employee of Celgene Corp., Summit, NJ. The remaining authors declare no competing financial interests.

To the Editor

The WHO defines chronic neutrophilic leukemia (CNL) as a myeloproliferative neoplasm (MPN) with sustained elevated neutrophils and <10% immature cells [1]. Recently, recurrent somatic mutations in the membrane proximal domain of CSF3R were reported in patients with CNL [2],[3]. CSF3R was mutated in 100% [3], SETBP1 33% [3] and CALR in 12.5% of WHO-defined cases of CNL [4]. We analyzed mutations in CSF3R, SETBP1 and CALR in 14 subjects who met the WHO-criteria.

Findings

CSF3R exon 14–17 [3], SETBP1 exon 4 [3] and CALR exon 9 [5] were amplified by PCR and sequenced. 8 subjects who met the WHO 2008 CNL criteria had a CSF3RT618I mutation, 6 SETBP1 mutations (2 D868N, 2 I871T, 1 G870S and 1 D874N) and the last had a CALR mutation (c.1154-1155insTTGTC). All mutations were heterozygous except 1 case of SETBP1I871T. 6 other subjects, 2 with monoclonal gammopathy of unknown significance (MGUS)-associated CNL and 4 with reactive neutrophilic leukocytosis had no mutation of these genes. No subject had a JAK2V617F mutation (Table 1).
Table 1
Clinical characteristics and laboratory variables
No.
Diagnosis
Gender/Age
Hb (g/L)
WBC (×109/L)
ANC (×109/L)
PLT (×109/L)
Spleen (cm,LCM)
Karyotypes
CSF3R
SETBP1
CALR
JAK2V617F
Treatment
Survival (month)
1
CNL
M/80
120
27.19
25.42
91
3
46,XY,t(1,7) (p32,q11)[10]
T618I
D874N
wt
wt
Hydroxyurea
52
2
CNL
M/64
123
86.83
ND
394
0
46,XY[5]
T618I
D868N
wt
wt
Hydroxyurea
5+
3
CNL
F/77
125
35.68
25.92
351
4
46,XY[20]
T618I
G870S
wt
wt
Hydroxyurea
22+
4
CNL
F/49
104
85.61
79.47
20
6
46,XX[20]
T618I
I871T
wt
wt
Hydroxyurea
13+
5
CNL
M/70
86
146.77
121.82
104
15
ND
T618I
I871T
wt
wt
Hydroxyurea
17
6
CNL
M/43
55
112.65
101.1
98
10
46,XY[5]
T618I
D868N
wt
wt
Hydroxyurea
4+
7
CNL
F/69
102
57.40
40.16
231
6
46,XX[12]
T618I
wt
c.1154-1155insTTGTC
wt
Hydroxyurea
10
8
CNL
M/45
119
32.76
28.73
286
6
46,XY[9]
T618I
wt
wt
wt
Hydroxyurea
32
9
MGUS-CNL
M/46
63
65.30
60.7
101
7
46,XY[2]
wt
wt
wt
wt
Hydroxyurea
6+
10
MGUS-CNL
F/52
121
26.53
19.94
170
3
46,XX[20]
wt
wt
wt
wt
Hydroxyurea
27+
All the parameters in Table 1 were measured at the initial diagnosis in our hospital.
MGUS-CNL: monoclonal gammopathy with uncertain significance associated CNL; Hb: hemoglobin; WBC: White Blood Cell Count; ANC: Absolute Neutrophil Count; PLT: Platelet Count; Spleen (cm): Spleen size under left costa. ND: not done.
The consistent association between CSF3RT618I and CNL in our study is similar to data of Maxson et al. [2] and Pardanani et al. [3] (Table 2). Tefferi et al.[6] suggested including CSF3RT618I or other membrane proximal CSF3R mutations as a criteria for diagnosis of CNL. We also confirmed the high incidence SETBP1 mutations in patients with CNL. The mutations we detected focused on a hotspot area from D868 to D874 (Table 1). Although these mutations also occur in other hematologic neoplasms such as atypical chronic myeloid leukemia aCML and chronic myelomonocytic leukemia (CMML), analysis of SETBP1 mutations could help distinguish CNL from reactive conditions such as infection, inflammatory conditions and non-haematologic neoplasms.
Table 2
CSF3R and SETBP1 mutations in CNL
 
Gotlib J et al. (2013) [[7]]
Pardanani A et al. (2013) [[3]]
This series
Total
T618I only
1
5
1
7
T618I + SETBP1
4
4
6
14
Compound CSF3R mutationsa only
2
1
0
3
Compound CSF3R mutations + SETBP1 mutations
1
0
0
1
Others
1b
2c
1d
4
a: compound CSF3R mutations mean nonsense or frameshift mutations that truncate the cytoplasmic tail (truncation mutations) combined with point mutations in the extracellular domain (membrane proximal mutation). In the 3 cases of compound CSF3R mutations Tyner et al. reported, two patients harbored T618I and one harbored T615A in the membrane proximal domain. In Tefferi's study, the compound CSF3R mutation showed T618I + c.2341_2342insC.
b: A case with JAK2 mutation only.
c: A case with I598I and a case with M696T in CSF3R.
d: A case with CSF3R T618I and CALR frameshift mutation.
Gotlib et al. reported JAK2V617F mutation in a subject of CNL [7]. Lasho et al. reported a CALR mis-sense mutation in a subject with CNL [4]. We found concurrent CSF3RT618I and CALR frame-shift mutations in 1 subject. The 5 bp insertion into CALR exon 9 is reported in BCR/ABL1- and JAK2-negative MPNs and results in a 1+ base-pair frame-shift with an altered C-terminus.
There is controversy whether co-existence of MGUS and CNL is one or two diseases. The 2 MGUS subjects in our study had no mutation in CSF3R, SETBP1, JAK2 or CALR. In another study, none of 6 cases of MGUS-associated CNL had CSF3R mutations [3]. Also, survival of patients with MGUS-associated CNL is significantly longer survival than those with CNL only. These data support the notion patients with MGUS and CNL are 2 diseases [8].
There may be therapy implications of our findings. CSF3R truncation mutations may be sensitive to SRC kinase-inhibitors such as dasatinib whereas CSF3R membrane proximal mutations may be sensitive to JAK kinase-inhibitors such as ruxolitinib [9],[10]. Ruxolitinib was reportedly effective in a mouse model of CNL and a patient with CNL and a CSF3RT618I mutation [2],[11]. However, ruxolitinib was ineffective in a patient with CSF3RT618I and SETBP1 mutations in whom fedratinib suppressed CFU-GM colony formation [12].

Authors’ contributions

XZJ designed the study and drafted the article. CYJ collected the data, analyzed the molecular aberrations, and drafted the article. RPG drafted the typescript. LB, JQ, XZF, QTJ, ZPH, and ZY reviewed the clinical and pathology data. All authors read and approved the final typescript.

Acknowledgements

Supported in part by National Natural Science Funds (No.81370611, No. 81270585), Tianjin Key Natural Science Funds (12JCZDJC23900), National Public Health Grand Research Foundation (No.201202017) (to ZX). RPG acknowledges support from the NIHR Biomedical Research Centre funding scheme.

Competing interests

RPG acknowledges support from the NIHR Biomedical Research Centre funding scheme and is a part-time employee of Celgene Corp., Summit, NJ. The remaining authors declare no competing financial interests.

Unsere Produktempfehlungen

e.Med Interdisziplinär

Kombi-Abonnement

Mit e.Med Interdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de. Zusätzlich können Sie eine Zeitschrift Ihrer Wahl in gedruckter Form beziehen – ohne Aufpreis.

e.Med Innere Medizin

Kombi-Abonnement

Mit e.Med Innere Medizin erhalten Sie Zugang zu CME-Fortbildungen des Fachgebietes Innere Medizin, den Premium-Inhalten der internistischen Fachzeitschriften, inklusive einer gedruckten internistischen Zeitschrift Ihrer Wahl.

e.Med Onkologie

Kombi-Abonnement

Mit e.Med Onkologie erhalten Sie Zugang zu CME-Fortbildungen des Fachgebietes Onkologie, den Premium-Inhalten der onkologischen Fachzeitschriften, inklusive einer gedruckten onkologischen Zeitschrift Ihrer Wahl.

Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 1/2014

Journal of Hematology & Oncology 1/2014 Zur Ausgabe

Neu im Fachgebiet Onkologie

Mail Icon II Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Onkologie und bleiben Sie gut informiert – ganz bequem per eMail.

Bildnachweise