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Bosutinib is a tyrosine kinase inhibitor undergoing research

We studied a three generation Caucasian pedigree in which 12 out of 16 individuals Bosutinib presented with a chronic neutrophilia associated with splenomegaly. The disorder was discovered in patient 15 during a unique episode of systemic inflammatory response syndrome that combined fever, tachycardia, dyspnea, pleural and pericardial effusion, hepatosplenomegaly, and weight loss. Biological features associated increased WBC counts by 102,000 cells/mm3, with 75% segmented neutrophils and 20% immature granulocytes, the hemoglobin level by 10 g/dl, and the platelet count by 101,000 cells/mm3. BM analysis revealed an increase in granulocyte precursors without an excess of blasts. Karyotype was normal. Bcr Abl transcripts and JAK2V617F were not detected. After this episode, patient 15 returned to chronic neutrophilia, but 18 mo later, he developed a myelodysplastic syndrome associating pancytopenia, skin infiltration by mature granulocytes, TGF-beta and 9% BM blasts. BM aspirate examination also showed a marked dysgranulopoiesis but no dyserythropoiesis or dysmegakaryopoiesis. A clonal abnormality was detected by a conventional cytogenetic in 70% of the metaphases. A fluorescent in situ hybridization analysis did not show evidence of EVI1 rearrangement. To eliminate a transcriptional activation of EVI1, we performed quantitative real time PCR. A 30% decrease in EVI1 mRNA was detected, suggesting that the deletion includes this gene. Familial history showed that 12 out of 16 members had a chronic neutrophilia. There was no evidence of consanguinity in this pedigree. In the 12 patients, median E7080 WBC counts were 21,350 cells/mm3 in peripheral blood, with >70% segmented neutrophils or band cells and <10% immature granulocytes. Median neutrophil counts were 16,900 cells/mm3. In the peripheral blood, a 3 to 20 fold increase in the percentage of circulating CD34 cells was observed. The BM of two analyzed affected individuals contained an increase in granulocyte precursors without an excess of blasts. The karyotype was normal; Bcr Abl transcripts and JAK2V617F were not detected. All affected patients except patient 15 had no clinical symptoms. Based on the autosomal dominant pattern of inheritance of the disorder and the high level of blood CD34 cells, we tested the hypothesis that neutrophilia in this family resulted from activation of the G CSF R signaling. Because G CSF concentration in the serum was below the detection limit, we sequenced the CSF3R gene. We found a heterozygous C to A substitution at nucleotide 2,088 that leads to a threonine to asparagine substitution. This heterozygous point mutation was observed in the 12 affected individuals but not in the 4 healthy family members, and was segregated with the neutrophilia. Moreover, the mutation was found in all generations and in as many affected men as women. Finally, the mutation was transmitted with an autosomal dominant pattern of inheritance with complete penetrance. The CSF3RT617N mutation has already been described as an activating mutation found in 2 out of 555 patients with acute myeloid leukemia. In these two cases, the mutation was acquired because it disappeared after complete remission achievement and was not detected at relapse. This last result demonstrates that the CSF3RT617N mutation was a secondary event in the leukemic process. We studied whether this mutation could be found in sporadic cases of unexplained neutrophilia and investigated 40 cases by allele specific PCR, but we did not find any other positive case suggesting that this activating mutation is rare. We studied a three generation Caucasian pedigree in which 12 out of 16 individuals presented with a chronic neutrophilia associated with splenomegaly. The disorder was discovered in patient 15 during a unique episode of systemic inflammatory response syndrome that combined fever, tachycardia, dyspnea, pleural and pericardial effusion, hepatosplenomegaly, and weight loss. Biological features associated increased WBC counts by 102,000 cells/mm3, with 75% segmented neutrophils and 20% immature granulocytes, the hemoglobin level by 10 g/dl, and the platelet count by 101,000 cells/mm3. BM analysis revealed an increase in granulocyte precursors without an excess of blasts. Karyotype was normal. Bcr Abl transcripts and JAK2V617F were not detected. After this episode, patient 15 returned to chronic neutrophilia, but 18 mo later, he developed a myelodysplastic syndrome associating pancytopenia, skin infiltration by mature granulocytes,  and 9% BM blasts. BM aspirate examination also showed a marked dysgranulopoiesis but no dyserythropoiesis or dysmegakaryopoiesis. A clonal abnormality was detected by a conventional cytogenetic in 70% of the metaphases. A fluorescent in situ hybridization analysis did not show evidence of EVI1 rearrangement. To eliminate a transcriptional activation of EVI1, we performed quantitative real time PCR. A 30% decrease in EVI1 mRNA was detected, suggesting that the deletion includes this gene. Familial history showed that 12 out of 16 members had a chronic neutrophilia. There was no evidence of consanguinity in this pedigree. In the 12 patients, median WBC counts were 21,350 cells/mm3 in peripheral blood, with >70% segmented neutrophils or band cells and <10% immature granulocytes. Median neutrophil counts were 16,900 cells/mm3. In the peripheral blood, a 3 to 20 fold increase in the percentage of circulating CD34 cells was observed. The BM of two analyzed affected individuals contained an increase in granulocyte precursors without an excess of blasts. The karyotype was normal; Bcr Abl transcripts and JAK2V617F were not detected. All affected patients except patient 15 had no clinical symptoms. Based on the autosomal dominant pattern of inheritance of the disorder and the high level of blood CD34 cells, we tested the hypothesis that neutrophilia in this family resulted from activation of the G CSF R signaling. Because G CSF concentration in the serum was below the detection limit, we sequenced the CSF3R gene. We found a heterozygous C to A substitution at nucleotide 2,088 that leads to a threonine to asparagine substitution. This heterozygous point mutation was observed in the 12 affected individuals but not in the 4 healthy family members, and was segregated with the neutrophilia. Moreover, the mutation was found in all generations and in as many affected men as women. Finally, the mutation was transmitted with an autosomal dominant pattern of inheritance with complete penetrance. The CSF3RT617N mutation has already been described as an activating mutation found in 2 out of 555 patients with acute myeloid leukemia. In these two cases, the mutation was acquired because it disappeared after complete remission achievement and was not detected at relapse. This last result demonstrates that the CSF3RT617N mutation was a secondary event in the leukemic process. We studied whether this mutation could be found in sporadic cases of unexplained neutrophilia and investigated 40 cases by allele specific PCR, but we did not find any other positive case suggesting that this activating mutation is rare.

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