Chronic neutrophilic leukemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Homa Najafi, M.D.[2]
Overview
The exact pathogenesis of Chronic neutrophilic leukemia (CNL) is not fully understood. Some cytogenic abnormalities like trisomy 7,8,9,21, deletion 11q, 20q6,7 may be seen in CNL patients. The mutation of CSF3R is seen in most patients. Moreover of mutation in CSF3R, there are some other genetic mutations which are less common.
Polycythemia vera, plasma cell disorders and nephrotic syndrome can be associated with CNL.
Pathophysiology
Pathogenesis
- It is understood that clonality has a role in the pathogenesis of CNL.[1] Cytogenetic abnormalities were seen in the diagnosis time or blast transformation
- In 2001, fewer than 150 cases of WHO-recognized CNL were reported in the literature, and the bulk of suspected CNL patients exhibited normal karyotype, with its clonal nature unproven. However, succeeding reports revealed nonspecific chromosomal abnormalities proposing monoclonality in CNL. These were observed either at the time of diagnosis or at the time of evolution to blast-phase disease.18,27,28 First proof of clonality of the leukemic neutrophils was substantiated by human androgen receptor gene assay in 5 female patients with CNL in 2003.2 Less than 50% of CNL patients display chromosomal abnormalities; the recurrent cytogenetic abnormalities included trisomy 8, trisomy 21, del(11q), and del(20q).18,27 Other nonspecific chromosomal abnormalities included deletion Y, and trisomy 7 and 9, which have likewise been documented in related myeloid malignancies
- Bohm et al recently provided evidence of clonality in CNL using the human androgen receptor gene assay (HUMARA), which assesses clonality of cells from female patients by examining the inactivation patterns of this gene on the X chromosome.5 Monoclonality was demonstrable in the neutrophils in 17 patients with different CMPD, including five patients withCNL. In four patients withCNL, autologous T cells were also monoclonal, suggesting that they belonged to the neoplastic clone. This finding was in contrast to the other CMPD they reported (including CML, aCML, CMML, PVand IMF) in which the neutrophils were monoclonal and the T cells were polyclonal. The authors suggested that in CNL the neoplastic transformation occurs at an earlier stage of progenitor differentiation than in other CMPD. However, other investigators have also demonstrated both myeloid and lymphocyte clonal involvement in CML,69,70 CIMF37, PV and ET71, consistent with CMPD originating in a pluripotent progenitor. The differences reported in locating the stage of clonal origin might reflect the sensitivity of the various assays to the less dominant lineage (lymphoid) involved. Although Bohm concluded that it was unlikely that the four of five CNL cases with monoclonal neutrophils and T cells represented ‘physiologic’skewing (as occurs in up to 40% of females over age 60), clonality assays using X-inactivation must be interpreted with caution
- The acquisition of additional molecular or cytogenetic abnormalities during clonal evolution has been reported in CNL18,156. The above mentioned study by Langabeer et al. using NGS also included analyses at the time of blastic transformation which identified clonal evolution in all patients as evidenced by increasing CSF3RT618I allele frequency or gain/loss of mutations156. The finding of NRAS mutations both at diagnosis and during blast crisis in this study provides a rationale for use of MEK inhibitors in CNL156. In the CNL patient having transformed to blastic phase in a study by Elliott et al., new karyotypic aberrations in the form of acquisition of monosomy 5 and 7 were also noted18. Another report additionally noted trisomy 21, deletion 12p, and monosomy 7 at the time of blast transformation in three of 12 CNL patients who were cytogenetically normal at baseline, though treatment with Hydroxyurea was postulated to have contributed to these karyotypic changes12. Recently, Nooruddin et al. provided valuable insight into the clonal evolution of CNL as acquisition of de novo mutations in KIT and GATA2 as well as increase in RUNX1 allele frequency were present in an index CNL patient at the time of disease progression and are posited to have driven clonal evolution135
- The cytogenetic abnormalities may be seen in CNL patients are:[2][3][4][5][6][7][8]
- Specific ones:
- non-specific ones:
- The progression to CNL usually involves the CSF3R mutation. CSF3R encodes the receptor of CSF3 that is neutrophilic growth factor. This mutation causes autonomous cell proliferation.[9][10]
Genetics
The development of CNL is the result of multiple genetic mutations such as:[11][2][12][13][14][15][16]
Associated Conditions
Conditions associated with CNL include:[17][18][19][20][21][22]
References
- ↑ J. Bohm, S. Kock, H. E. Schaefer & P. Fisch (2003). "Evidence of clonality in chronic neutrophilic leukaemia". Journal of clinical pathology. 56 (4): 292–295. PMID 12663642. Unknown parameter
|month=ignored (help) - ↑ 2.0 2.1 Elliott, Michelle A.; Pardanani, Animesh; Hanson, Curtis A.; Lasho, Terra L.; Finke, Christy M.; Belachew, Alem A.; Tefferi, Ayalew (2015). "ASXL1mutations are frequent and prognostically detrimental inCSF3R-mutated chronic neutrophilic leukemia". American Journal of Hematology. 90 (7): 653–656. doi:10.1002/ajh.24031. ISSN 0361-8609.
- ↑ John T. Reilly (2002). "Chronic neutrophilic leukaemia: a distinct clinical entity?". British journal of haematology. 116 (1): 10–18. PMID 11841395. Unknown parameter
|month=ignored (help) - ↑ Piliotis, E.; Kutas, G.; Lipton, J.H. (2009). "Allogeneic Bone Marrow Transplantation in the Management of Chronic Neutrophilic Leukemia". Leukemia & Lymphoma. 43 (10): 2051–2054. doi:10.1080/1042819021000016087. ISSN 1042-8194.
- ↑ Elliott, M A; Hanson, C A; Dewald, G W; Smoley, S A; Lasho, T L; Tefferi, A (2004). "WHO-defined chronic neutrophilic leukemia: a long-term analysis of 12 cases and a critical review of the literature". Leukemia. 19 (2): 313–317. doi:10.1038/sj.leu.2403562. ISSN 0887-6924.
- ↑ Donato, Carlo Di; Croci, Gianfranco; Lazzari, Stefano; Scarduelli, Laura; Vignoli, Roberto; Buia, Marco; Tramaloni, Casimiro; Maccari, Sergio; Plancher, Angelo Cesare (1986). "Chronic Neutrophilic Leukemia: Description of a New Case with Karyotypic Abnormalities". American Journal of Clinical Pathology. 85 (3): 369–371. doi:10.1093/ajcp/85.3.369. ISSN 1943-7722.
- ↑ Michelle A. Elliott (2004). "Chronic neutrophilic leukemia: a contemporary review". Current hematology reports. 3 (3): 210–217. PMID 15087070. Unknown parameter
|month=ignored (help) - ↑ Donald P. Mc Lornan, Melanie J. Percy, Amy V. Jones, Nicholas C. P. Cross & Mary Frances Mc Mullin (2005). "Chronic neutrophilic leukemia with an associated V617F JAK2 tyrosine kinase mutation". Haematologica. 90 (12): 1696–1697. PMID 16330446. Unknown parameter
|month=ignored (help) - ↑ Beekman, R.; Valkhof, M. G.; Sanders, M. A.; van Strien, P. M. H.; Haanstra, J. R.; Broeders, L.; Geertsma-Kleinekoort, W. M.; Veerman, A. J. P.; Valk, P. J. M.; Verhaak, R. G.; Lowenberg, B.; Touw, I. P. (2012). "Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia". Blood. 119 (22): 5071–5077. doi:10.1182/blood-2012-01-406116. ISSN 0006-4971.
- ↑ Dong, Fan; Brynes, Russell K.; Tidow, Nicola; Welte, Karl; Löwenberg, Bob; Touw, Ivo P. (1995). "Mutations in the Gene for the Granulocyte Colony-Stimulating–Factor Receptor in Patients with Acute Myeloid Leukemia Preceded by Severe Congenital Neutropenia". New England Journal of Medicine. 333 (8): 487–493. doi:10.1056/NEJM199508243330804. ISSN 0028-4793.
- ↑ Pardanani, A; Lasho, T L; Laborde, R R; Elliott, M; Hanson, C A; Knudson, R A; Ketterling, R P; Maxson, J E; Tyner, J W; Tefferi, A (2013). "CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia". Leukemia. 27 (9): 1870–1873. doi:10.1038/leu.2013.122. ISSN 0887-6924.
- ↑ Maxson, Julia E.; Gotlib, Jason; Pollyea, Daniel A.; Fleischman, Angela G.; Agarwal, Anupriya; Eide, Christopher A.; Bottomly, Daniel; Wilmot, Beth; McWeeney, Shannon K.; Tognon, Cristina E.; Pond, J. Blake; Collins, Robert H.; Goueli, Basem; Oh, Stephen T.; Deininger, Michael W.; Chang, Bill H.; Loriaux, Marc M.; Druker, Brian J.; Tyner, Jeffrey W. (2013). "Oncogenic CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML". New England Journal of Medicine. 368 (19): 1781–1790. doi:10.1056/NEJMoa1214514. ISSN 0028-4793.
- ↑ Gotlib, J.; Maxson, J. E.; George, T. I.; Tyner, J. W. (2013). "The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment". Blood. 122 (10): 1707–1711. doi:10.1182/blood-2013-05-500959. ISSN 0006-4971.
- ↑ Meggendorfer, M.; Haferlach, T.; Alpermann, T.; Jeromin, S.; Haferlach, C.; Kern, W.; Schnittger, S. (2014). "Specific molecular mutation patterns delineate chronic neutrophilic leukemia, atypical chronic myeloid leukemia, and chronic myelomonocytic leukemia". Haematologica. 99 (12): e244–e246. doi:10.3324/haematol.2014.113159. ISSN 0390-6078.
- ↑ Cui, Yajuan; Li, Bing; Gale, Robert Peter; Jiang, Qian; Xu, Zefeng; Qin, Tiejun; Zhang, Peihong; Zhang, Yue; Xiao, Zhijian (2014). "CSF3R, SETBP1 and CALR mutations in chronic neutrophilic leukemia". Journal of Hematology & Oncology. 7 (1). doi:10.1186/s13045-014-0077-1. ISSN 1756-8722.
- ↑ Dao, K.-H. T.; Tyner, J. W. (2015). "What's different about atypical CML and chronic neutrophilic leukemia?". Hematology. 2015 (1): 264–271. doi:10.1182/asheducation-2015.1.264. ISSN 1520-4391.
- ↑ Rending Wang, Hongyan Tong, Huiping Wang, Zhimin Chen, Lijun Wang & Jianghua Chen (2014). "Nephrotic syndrome related to chronic neutrophilic leukemia". Internal medicine (Tokyo, Japan). 53 (21): 2505–2509. PMID 25366011.
- ↑ Bain, Barbara J.; Ahmad, Shahzaib (2015). "Chronic neutrophilic leukaemia and plasma cell-related neutrophilic leukaemoid reactions". British Journal of Haematology. 171 (3): 400–410. doi:10.1111/bjh.13600. ISSN 0007-1048.
- ↑ Higuchi, Takakazu; Oba, Remi; Endo, Mitsue; Harada, Hiroshi; Mori, Hiraku; Niikura, Haruo; Omine, Mitsuhiro; Fujita, Kazuhiro (2009). "Transition of Polycythemia Vera to Chronic Neutrophilic Leukemia". Leukemia & Lymphoma. 33 (1–2): 203–206. doi:10.3109/10428199909093744. ISSN 1042-8194.
- ↑ Lee, Seung Soon; Moon, Joon Ho; Ha, Jun Wook; Lee, Young Kyung; Ahn, Jin Seok; Zang, Dae Young; Kim, Hyo Jung (2004). "A Case of Transition of Polycythemia Vera to Chronic Neutrophilic Leukemia". The Korean Journal of Internal Medicine. 19 (4): 285–288. doi:10.3904/kjim.2004.19.4.285. ISSN 1226-3303.
- ↑ Cehreli, Cavit; Undar, Bulent; Akkoc, Nurullah; Onvural, Banu; Altungoz, Oguz (1994). "Coexistence of Chronic Neutrophilic Leukemia with Light Chain Myeloma". Acta Haematologica. 91 (1): 32–34. doi:10.1159/000204241. ISSN 0001-5792.
- ↑ DinÇol, GünÇağ; NalÇacI, Meliha; Doğan, Öner; Aktan, Melih; KüÇükkaya, Reyhan; Ağan, Mehmet; DinÇol, Koray (2009). "Coexistence of Chronic Neutrophilic Leukemia with Multiple Myeloma". Leukemia & Lymphoma. 43 (3): 649–651. doi:10.1080/10428190290012218. ISSN 1042-8194.