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T618I-Mutated Colony Stimulating Factor 3 Receptor in Chronic Neutrophilic Leukemia and Chronic Myelomonocytic Leukemia Patients who Underwent Allogeneic Stem Cell Transplantation.

Lee SE, Jo I, Jang W, Kim Y, Han K, Kim M - Ann Lab Med (2015)

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea.

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Dear Editor Recently, the mutations within the colony-stimulating factor 3 receptor gene (CSF3R) have been reported as a specific marker of chronic neutrophilic leukemia (CNL) and atypical CML (aCML)... Here, we describe two CSF3R T618I-mutated patients with CNL and CMML, respectively, who underwent allogeneic stem cell transplantation (allo-SCT)... However, his neutrophilia persisted in the peripheral blood as anemia and thrombocytopenia developed... Repeated BM examinations showed hypercellular BM with granulocytic hyperplasia and decreased megakaryocytes, and a clonal chromosomal abnormality of 46,XY,der(18:21)(q10;q10),+21[7]/47,+21[5]/46,XY[8]... The CSF3R T618I mutation was identified through direct sequencing (Fig. 2B)... An initial azacitidine treatment failed to achieve any response... Since high-frequency of CSF3R mutations in CNL (89%) and, to a lesser extent, in aCML (40%) were discovered, Pardanani et al. has confirmed that the CSF3R T618I mutation was detected exclusively in cases of WHO-defined CNL, with a mutational frequency of 83%... Previous studies showed discordant frequencies in the CSF3R mutations in CMML and aCML... Although CSF3R mutations have been observed in 4% of patients with CMML, they are distinct from membrane proximal mutations; the T618I mutation was identified in a majority of patients with CNL... Although there is no current standard of care for CNL or for aCML, allo-SCT may be applicable to young patients with potential for blast transformation and progressive refractory neutrophilia... In our two CNL and CMML patients harboring the CSF3R T618I mutation, and who had undergone allo-SCT, the CSF3R T618I mutation was not detected following allo-SCT... This suggests a predictive role of this mutation in post-transplant relapse, supported by prior studies showing a correlation between post-transplant relapse and the persistence of the CSF3R T618I in aCML... Thus, testing for the CSF3R mutation may lead to genetically informed therapy and useful diagnostic approach... The influence of the CSF3R mutations on genotype-phenotype associations, disease prognosis, and the efficacy of the therapeutic inhibition of CSF3R-related signaling needs to be clarified.

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Chronic neutrophilic leukemia; (A) peripheral blood showing neutrophilia with toxic granulation (Wright-Giemsa staining, ×1,000) and (B) bone marrow biopsy showing a markedly elevated myeloid:erythroid ratio. Chronic myelomonocytic leukemia (Hematoxylin and eosin staining, ×1,000); (C) peripheral blood with monocytosis and neutrophilia (Wright-Giemsa staining, ×400) and (D) bone marrow aspirate with erythroid and granulocytic dysplasia (Wright-Giemsa staining, ×1,000).
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Figure 1: Chronic neutrophilic leukemia; (A) peripheral blood showing neutrophilia with toxic granulation (Wright-Giemsa staining, ×1,000) and (B) bone marrow biopsy showing a markedly elevated myeloid:erythroid ratio. Chronic myelomonocytic leukemia (Hematoxylin and eosin staining, ×1,000); (C) peripheral blood with monocytosis and neutrophilia (Wright-Giemsa staining, ×400) and (D) bone marrow aspirate with erythroid and granulocytic dysplasia (Wright-Giemsa staining, ×1,000).

Mentions: A 40-yr-old man presented in 2012 with marked neutrophilia. His total white blood cell count was 77.24×109/L with a differential of 80% neutrophils, 3% band forms, 3% metamyelocytes, 1% myelocytes, 1% promyelocytes, 1% blasts, 3% lymphocytes, and 10% monocytes (Fig. 1A). He had a 23-cm splenomegaly. His bone marrow (BM) aspirate and biopsy showed hypercellularity with granulocytic hyperplasia (Fig. 1B), with a normal karyotype and no evidence of BCR-ABL1, PDGFRA, or PDGFRB rearrangement when examined by FISH. Molecular studies demonstrated the absence of JAK2 V617F and BCR-ABL1 transcripts. CNL was diagnosed in accordance with the WHO diagnostic criteria, and the patient was treated with hydroxyurea. However, his neutrophilia persisted in the peripheral blood as anemia and thrombocytopenia developed. Repeated BM examinations showed hypercellular BM with granulocytic hyperplasia and decreased megakaryocytes, and a clonal chromosomal abnormality of 46,XY,der(18:21)(q10;q10),+21[7]/47,+21[5]/46,XY[8]. The CSF3R T618I mutation was detected (Fig. 2A). He then underwent myeloablative allo-SCT, using cells from an unrelated donor. At day 35 following the allo-SCT, BM examination showed 70% cellularity with 100% donor chimerism. The T618I mutation was not detected in the BM aspirates through sequencing (Fig. 2C).


T618I-Mutated Colony Stimulating Factor 3 Receptor in Chronic Neutrophilic Leukemia and Chronic Myelomonocytic Leukemia Patients who Underwent Allogeneic Stem Cell Transplantation.

Lee SE, Jo I, Jang W, Kim Y, Han K, Kim M - Ann Lab Med (2015)

Chronic neutrophilic leukemia; (A) peripheral blood showing neutrophilia with toxic granulation (Wright-Giemsa staining, ×1,000) and (B) bone marrow biopsy showing a markedly elevated myeloid:erythroid ratio. Chronic myelomonocytic leukemia (Hematoxylin and eosin staining, ×1,000); (C) peripheral blood with monocytosis and neutrophilia (Wright-Giemsa staining, ×400) and (D) bone marrow aspirate with erythroid and granulocytic dysplasia (Wright-Giemsa staining, ×1,000).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390711&req=5

Figure 1: Chronic neutrophilic leukemia; (A) peripheral blood showing neutrophilia with toxic granulation (Wright-Giemsa staining, ×1,000) and (B) bone marrow biopsy showing a markedly elevated myeloid:erythroid ratio. Chronic myelomonocytic leukemia (Hematoxylin and eosin staining, ×1,000); (C) peripheral blood with monocytosis and neutrophilia (Wright-Giemsa staining, ×400) and (D) bone marrow aspirate with erythroid and granulocytic dysplasia (Wright-Giemsa staining, ×1,000).
Mentions: A 40-yr-old man presented in 2012 with marked neutrophilia. His total white blood cell count was 77.24×109/L with a differential of 80% neutrophils, 3% band forms, 3% metamyelocytes, 1% myelocytes, 1% promyelocytes, 1% blasts, 3% lymphocytes, and 10% monocytes (Fig. 1A). He had a 23-cm splenomegaly. His bone marrow (BM) aspirate and biopsy showed hypercellularity with granulocytic hyperplasia (Fig. 1B), with a normal karyotype and no evidence of BCR-ABL1, PDGFRA, or PDGFRB rearrangement when examined by FISH. Molecular studies demonstrated the absence of JAK2 V617F and BCR-ABL1 transcripts. CNL was diagnosed in accordance with the WHO diagnostic criteria, and the patient was treated with hydroxyurea. However, his neutrophilia persisted in the peripheral blood as anemia and thrombocytopenia developed. Repeated BM examinations showed hypercellular BM with granulocytic hyperplasia and decreased megakaryocytes, and a clonal chromosomal abnormality of 46,XY,der(18:21)(q10;q10),+21[7]/47,+21[5]/46,XY[8]. The CSF3R T618I mutation was detected (Fig. 2A). He then underwent myeloablative allo-SCT, using cells from an unrelated donor. At day 35 following the allo-SCT, BM examination showed 70% cellularity with 100% donor chimerism. The T618I mutation was not detected in the BM aspirates through sequencing (Fig. 2C).

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Dear Editor Recently, the mutations within the colony-stimulating factor 3 receptor gene (CSF3R) have been reported as a specific marker of chronic neutrophilic leukemia (CNL) and atypical CML (aCML)... Here, we describe two CSF3R T618I-mutated patients with CNL and CMML, respectively, who underwent allogeneic stem cell transplantation (allo-SCT)... However, his neutrophilia persisted in the peripheral blood as anemia and thrombocytopenia developed... Repeated BM examinations showed hypercellular BM with granulocytic hyperplasia and decreased megakaryocytes, and a clonal chromosomal abnormality of 46,XY,der(18:21)(q10;q10),+21[7]/47,+21[5]/46,XY[8]... The CSF3R T618I mutation was identified through direct sequencing (Fig. 2B)... An initial azacitidine treatment failed to achieve any response... Since high-frequency of CSF3R mutations in CNL (89%) and, to a lesser extent, in aCML (40%) were discovered, Pardanani et al. has confirmed that the CSF3R T618I mutation was detected exclusively in cases of WHO-defined CNL, with a mutational frequency of 83%... Previous studies showed discordant frequencies in the CSF3R mutations in CMML and aCML... Although CSF3R mutations have been observed in 4% of patients with CMML, they are distinct from membrane proximal mutations; the T618I mutation was identified in a majority of patients with CNL... Although there is no current standard of care for CNL or for aCML, allo-SCT may be applicable to young patients with potential for blast transformation and progressive refractory neutrophilia... In our two CNL and CMML patients harboring the CSF3R T618I mutation, and who had undergone allo-SCT, the CSF3R T618I mutation was not detected following allo-SCT... This suggests a predictive role of this mutation in post-transplant relapse, supported by prior studies showing a correlation between post-transplant relapse and the persistence of the CSF3R T618I in aCML... Thus, testing for the CSF3R mutation may lead to genetically informed therapy and useful diagnostic approach... The influence of the CSF3R mutations on genotype-phenotype associations, disease prognosis, and the efficacy of the therapeutic inhibition of CSF3R-related signaling needs to be clarified.

No MeSH data available.


Related in: MedlinePlus