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 JAK2
V617F mutation (Table
1).
Table 1
Clinical characteristics and laboratory variables
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+ |
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
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 |
Gotlib
et al. reported JAK2
V617F 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.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
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.