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Myeloproliferative Neoplasms (MPN)
Published in Dongyou Liu, Tumors and Cancers, 2017
MPN (formerly myeloproliferative disorders or MPD) are a group of diseases characterized by the overproduction of one or more blood cell types (red cells, white cells, or platelets) by the bone marrow. MPN may be further separated into nine subgroups: (i) chronic myeloid leukemia (CML; BCR-ABL1+ gene), (ii) chronic neutrophilic leukemia (CNL), (iii) polycythemia vera (PV), (iv) primary myelofibrosis (PMF), (v) PMF—prefibrotic/early stage, (vi) PMF—overt fibrotic stage, (vii) essential thrombocythemia (ET), (viii) chronic eosinophilic leukemia not otherwise specified (CEL-NOS), and (ix) MPN—unclassifiable (see Table 13.1) [2].
Other Myeloproliferative Neoplasms
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
Chronic neutrophilic leukemia (CNL) is a rare and distinct BCR–ABL-negative chronic MPN defined by sustained (mature) neutrophilia [1,48–51]. It affects mostly elderly patients. The diagnostic criteria of CNL include (1) peripheral blood neutrophilic leukocytosis (≥25 × 109/L) with segmented neutrophils and bands (>80%), myeloblasts (<1%), and immature granulocytes (promyelocytes, myelocytes, and metamyelocytes) (<10%); (2) hypercellular BM with a normalmaturation pattern, myeloblasts (<5%), and an increased M:E ratio; (3) hepatosplenomegaly; (4) no identifiable secondary etiology for neutrophilia; (5) lack of Philadelphia chromosome (BCR–ABL fusion); (6) lack of rearrangement of PDGFRA, PDGFRB, or FGFR1; (7) no evidence of classic chronic MPN (PV, ET, or PMF); and (8) no evidence of MDS (features of dyspoiesis) or monocytosis (monocytes <1 × 109/L) [1].
BCR-ABL as a Molecular Target
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
The breakpoints in BCR localize to the so-called breakpoint cluster regions (bcr), a fact that is reflected in the gene’s name. Depending on where the breaks occur, variable parts of BCR are conserved in the Bcr-Abl fusion protein, leading to proteins of different size. Unlike in BCR, the breakpoints in ABL are spread over a wide genomic region and may occur anywhere upstream of ABL exon Ib, downstream of exon Ia, or between the two alternative first exons (Fig. 1). Due to splicing of the primary mRNA, the BCR portion is almost invariably fused to ABL exon 2, with rare exceptions (10). Three bcrs can be distinguished. Breakpoints in the major bcr (M-bcr) conserve BCR sequences up to exon 13 or 14 (formerly referred to as b2 and b3), which give rise to e13a2 or e14a2 mRNAs and lead to the expression of a 210 kD Bcr-Abl protein (p210Bcr-Abl). The latter is found in almost all CML patients and approximately one-third of the ALL patients. Breaks in the minor breakpoint cluster region (m-bcr) conserve only BCR exon 1, yielding an e1a2 mRNA and smaller 185 kD Bcr-Abl protein (p185Bcr-Abl) that is characteristic of ALL and which is only very rarely found in CML (10). A third breakpoint cluster region termed μ-bcr is located toward the 3’ end of BCR. Breaks in this region conserve most BCR sequences and lead to expression of an e19a2 BCR-AML mRNA and a 230 kD protein that is associated with chronic neutrophilic leukemia, a rather benign condition (10). Altogether, the preservation of longer Bcr sequences in the Bcr-Abl fusion protein appears to attenuate the disease.
Secondary chronic myeloid leukemia following acute myeloid leukemia treated with autologous hematopoietic stem cell transplantation: a case report
Published in Current Medical Research and Opinion, 2020
Jing Cheng, Yaping Liao, Ting Bin, Juan OUYang, Shaoqian Chen, Xueyan Chen, Waiyi Zou
CML, a biphasic hematopoietic stem cell-derived but progenitor-driven myeloproliferative disorder characterized by the accumulation of apparently normal myeloid cells, is caused by exposure to harmful environmental conditions or genetic predisposition11. Up to 50% of patients demonstrate symptoms and are incidentally diagnosed after routine laboratory evaluation. Clinical features are usually nonspecific: splenomegaly is present in 46–76%12. The distinctive features of CML are the Philadelphia (Ph) chromosome that originates from the reciprocal translocation t(9;22)(q34;q11.2). It determines the constitutively active BCR/ABL1 oncogenic tyrosine kinase whose expression is essential for the initiation, maintenance and progression of the disease13,14. Other than the clinical symptoms, the presentation of this case was consistent with typical CML. Meanwhile, chronic neutrophilic leukemia (CNL) is strongly associated with the presence of CSF3R mutations, negative CSF3R-mutation and positive Ph-chromosome, which can easily separate CML from CNL.
Clonal evolution in a chronic neutrophilic leukemia patient
Published in Hematology, 2019
Qi-Guo Zhang, Jing Wang, Wen-Yu Gong, Qi-Chuan Jin
Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R); these mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. The WHO classification was updated in 2016 to activating mutations of CSF3R, such as CSF3R T618I, as a diagnostic tool. Two classes of mutations in CSF3R were identified: membrane-proximal mutations located in exon 14 and truncation mutations located in exon 17 [1]. Both types of mutations were shown to possess in vitro transforming capacity, which is mediated via different downstream signaling pathways. Here, we describe the disease pathogenesis of an index CNL patient during a follow-up by identifying the clonal evolution.
Chronic neutrophilic leukemia
Published in Baylor University Medical Center Proceedings, 2018
Arthur Bredeweg, Micah Burch, John R. Krause
A 53-year-old man presented to the emergency room with abdominal pain. He was a previous smoker (50 pack-years) and stated that he had recently been experiencing night sweats. The past history was otherwise unremarkable. Blood work at the time revealed a leukocytosis of 40 × 109/L (Figure 1a) and hyperuricemia (10.1 mg/dL). Mild splenomegaly was present. Flow cytometry detected a very small (0.1) population of kappa clonal plasma cells. A bone marrow examination showed a hypercellular (100%) marrow with granulocytic hyperplasia and numerous polymorphonuclear cells (Figures 1b and 1c). A plasma cell infiltrate was not appreciated. Subsequent lab work revealed the absence of the BCR/ABL oncoprotein but the presence of colony-stimulating factor 3 receptor (CSF3R) and set binding protein 1 (SETBP1) mutations. These findings were consistent with a diagnosis of chronic neutrophilic leukemia (CNL). The patient was started on ruxolitinib and scheduled for follow-up.