Skip to main content

Advertisement

CSF3R, SETBP1 and CALR mutations in chronic neutrophilic leukemia

Article metrics

  • 3199 Accesses

  • 20 Citations

Abstract

The WHO 2008 definition of chronic neutrophilic leukemia (CNL) is based on clinical and laboratory parameters but not on molecular abnormalities. Mutations in CSF3R, SETBP1 and CALR are reported in patients with chronic neutrophilic leukemia (CNL). However, because CNL is rare, there are few large studies of this issue. We sequenced these genes in 14 patients who met the WHO-criteria of CNL. 8 subjects had CSF3RT618I, 6 SETBP1 mutations and 1 a CALR mutation. Our data suggest mutation analysis of CSF3R, SETBP1 and CALR should be included in the diagnostic criteria for CNL. These data may also have therapy implications.

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

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 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.

References

  1. 1.

    Bain BJ, Brunning RD, Vardiman JW, Thiele J: Chronic neutrophilic leukemia. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Edited by: Swerdlow SH, Campo E, Lee Harris N. 2008, IARC Press, Lyon, France, 38-39.

  2. 2.

    Maxson JE, Gotlib J, Pollyea DA, Fleischman AG, Agarwal A, Eide CA, Bottomly D, Wilmot B, McWeeney SK, Tognon CE, Pond JB, Collins RH, Goueli B, Oh ST, Deininger MW, Chang BH, Loriaux MM, Druker BJ, Tyner JW: Oncogenic csf3r mutations in chronic neutrophilic leukemia and atypical cml. N Engl J Med. 2013, 368 (19): 1781-1790. 10.1056/NEJMoa1214514.

  3. 3.

    Pardanani A, Lasho TL, Laborde RR, Elliott M, Hanson CA, Knudson RA, Ketterling RP, Maxson JE, Tyner JW, Tefferi A: CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia. Leukemia. 2013, 27 (9): 1870-1873. 10.1038/leu.2013.122.

  4. 4.

    Lasho TL, Elliott MA, Pardanani A, Tefferi A: CALR mutation studies in chronic neutrophilic leukemia. Am J Hematol. 2014, 89 (4): 450-10.1002/ajh.23665.

  5. 5.

    Li B, Xu J, Wang J, Gale RP, Xu Z, Cui Y, Yang L, Xing R, Ai X, Qin T, Zhang Y, Zhang P, Xiao Z: Calreticulin mutations in chinese with primary myelofibrosis. Haematologica. 2014, [Epub ahead of print]

  6. 6.

    Tefferi A, Thiele J, Vannucchi AM, Barbui T: An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia. 2014, 28 (7): 1407-1413. 10.1038/leu.2014.35.

  7. 7.

    Gotlib J, Maxson JE, George TI, Tyner JW: The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment. Blood. 2013, 122 (10): 1707-1711. 10.1182/blood-2013-05-500959.

  8. 8.

    Elliott MA, Dewald GW, Tefferi A, Hanson CA: Chronic neutrophilic leukemia (CNL): a clinical, pathologic and cytogenetic study. Leukemia. 2001, 15 (1): 35-40. 10.1038/sj.leu.2401993.

  9. 9.

    Nicholson SE, Oates AC, Harpur AG, Ziemiecki A, Wilks AF, Layton JE: Tyrosine kinase JAK1 is associated with the granulocyte-colony-stimulating factor receptor and both become tyrosine-phosphorylated after receptor activation. Proc Natl Acad Sci U S A. 1994, 91 (8): 2985-2988. 10.1073/pnas.91.8.2985.

  10. 10.

    Corey SJ, Burkhardt AL, Bolen JB, Geahlen RL, Tkatch LS, Tweardy DJ: Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases. Proc Natl Acad Sci U S A. 1994, 91 (11): 4683-4687. 10.1073/pnas.91.11.4683.

  11. 11.

    Fleischman AG, Maxson JE, Luty SB, Agarwal A, Royer LR, Abel ML, MacManiman JD, Loriaux MM, Druker BJ, Tyner JW: The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition. Blood. 2013, 122 (22): 3628-3631. 10.1182/blood-2013-06-509976.

  12. 12.

    Lasho TL, Mims A, Elliott MA, Finke C, Pardanani A, Tefferi A: Chronic neutrophilic leukemia with concurrent CSF3R and SETBP1 mutations: single colony clonality studies, in vitro sensitivity to JAK inhibitors and lack of treatment response to ruxolitinib. Leukemia. 2014, 28 (6): 1363-1365. 10.1038/leu.2014.39.

Download references

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.

Author information

Correspondence to Zhijian Xiao.

Additional information

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cui, Y., Li, B., Gale, R.P. et al. CSF3R, SETBP1 and CALR mutations in chronic neutrophilic leukemia. J Hematol Oncol 7, 77 (2014) doi:10.1186/s13045-014-0077-1

Download citation

Keywords

  • Chronic neutrophilic leukemia, CNL
  • CSF3R
  • SETBP1
  • CALR
  • Mutation