Immunophenotypic normalization of aberrant mast cells accompanies histological remission in imatinib-treated patients with eosinophilia-associated mastocytosis

Elliott, Michelle A.; Pardanani, Animesh; Li, C. Y.; Tefferi, Ayalew

doi:10.1038/sj.leu.2403329

Cited by 18 publications

(17 citation statements)

References 6 publications

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“…In rare instances, MC development is subverted to cause mastocytosis or MCL, usually as a result of a somatically-acquired c-Kit mutation(14,58). However, a subset of pediatric and aggressive MC dyscrasias do not have c-Kit mutations, and MCL often loses c-Kit mutations(15,60). Here, we ascribe an important function to the RNA binding protein Lin28 in MC development and associate upregulation of this protein with aggressive mast cell malignancy.…”

Section: Discussionmentioning

confidence: 99%

The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

et al. 2015

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Mast cells are critical components of the innate immune system and important for host defense, allergy, autoimmunity, tissue regeneration, and tumor progression. Dysregulated mast cell development leads to systemic mastocytosis, a clinically variable but often devastating family of hematologic disorders. Here we report that induced expression of Lin28, a heterochronic gene and pluripotency factor implicated in driving a fetal hematopoietic program, caused mast cell accumulation in adult mice in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in LIN28B-expressing hematopoietic progenitors, with increased levels of LIN28B in common myeloid and basophil-mast cell progenitors altering gene expression patterns to favor cell fate choices that enhanced mast cell specification. In addition, LIN28B-induced mast cells appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of mast cell terminal differentiation in the context of LIN28B upregulation. Finally, interrogation of human mast cell leukemia samples revealed upregulation of LIN28B in abnormal mast cells from patients with systemic mastocytosis (SM). This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in mast cell disease.

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Section: Discussionmentioning

confidence: 99%

The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

et al. 2015

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“…Time to complete hematologic response (defined as normalization of complete blood count, white blood cell differential, and eosinophil count) varied from 1 to 6 weeks. In addition, posttreatment bone marrow examinations, when performed, showed equally impressive improvements, including decreased cellularity, resolution of abnormal mast cell infiltration, 74 and reversal of myelofibrosis. 17,20,46 Furthermore, molecular remission was documented by FISH in 4 patients 20 and by RT-PCR in 7 patients.…”

Section: Pardanani and Tefferimentioning

confidence: 94%

Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders

Pardanani

Tefferi

2004

Blood

119

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Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet-derived growth factor receptor A and B (PDGFRA and PDGFRB) tyrosine kinases. The drug has acquired therapeutic relevance because of similar inhibitory activity against certain activating mutations of these molecular targets. The archetypical disease in this regard is chronic myeloid leukemia, where abl is constitutively activated by fusion with the bcr gene (bcr/abl).Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene. The former usually results from translocations involving chromosome 5q31-33, and the latter usually results from an interstitial deletion involving chromosome 4q12 (FIP1L1-PDGFRA). In contrast, imatinib is ineffective, in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation. However, wild-type and other c-kit mutations might be vulnerable to the drug, as has been the case in gastrointestinal stomal cell tumors. Imatinib is considered investigational for the treatment of hematologic malignancies without a defined molecular drug target, such as polycythemia vera, myelofibrosis with myeloid metaplasia, and acute myeloid leukemia.

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“…In the largest study to date of imatinib therapy in FIP1L1-PDGFRA + clonal eosinophilia, all 8 treated patients achieved complete as well as durable (4–30 months) remissions with relatively low drug dose levels (100 mg/day) [12, 32, 33]. The experience from other investigators was similar and clinical remissions were often accompanied by histological and molecular remisssion [16, 31,47,48,49,50,51].…”

Section: Current Diagnostic Evaluation Of Primary Eosinophiliamentioning

confidence: 96%

“…For example, cytogenetic studies do not detect the usual PDGFRA rearrangement that is a result of an interstitial chromosome 4q12 deletion that causes FIP1L1-PDGFRA + SM [31,][32]. This must be sought with either a fluorescence in situ hybridization or reverse-transcriptase-polymerase-chain-reaction-based laboratory technique [33]. At present, I recommend performing either fluorescence in situ hybridization or reverse transcriptase-polymerase chain reaction for detecting FIP1L1-PDGFRA in all patients with prominent blood eosinophilia and those who are suspected of having either SM or HES.…”

Section: Current Diagnostic Evaluation Of Primary Eosinophiliamentioning

confidence: 99%

Modern Diagnosis and Treatment of Primary Eosinophilia

Tefferi

2005

Acta Haematol

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The recent discovery of an eosinophilia-specific, imatinib-sensitive, karyotypically occult but fluorescence in situ hybridization-apparent molecular lesion in a subset of patients with blood eosinophilia has transformed the diagnostic as well as treatment approach to eosinophilic disorders. Primary (i.e. nonreactive) eosinophilia is considered either ‘clonal’ or ‘idiopathic’ based on the presence or absence, respectively, of either a molecular or bone marrow histological evidence for a myeloid neoplasm. Clonal eosinophilia might accompany a spectrum of clinicopathological entities, the minority of whom are molecularly characterized; Fip1-like-1-platelet-derived growth factor receptor α (FIP1L1-PDGFRA⁺) systemic mastocytosis, platelet-derived growth factor receptor β (PDGFRB)-rearranged atypical myeloproliferative disorder, chronic myeloid leukemia, and the 8p11 syndrome that is associated with fibroblast growth factor receptor 1 (FGFR1) rearrangement. Hypereosinophilic syndrome (HES) is a subcategory of idiopathic eosinophilia and is characterized by an absolute eosinophil count of ≧1.5 × 10⁹/l for at least 6 months as well as eosinophil-mediated tissue damage. At present, a working diagnosis of primary eosinophilia mandates a bone marrow examination, karyotype analysis, and additional molecular studies in order to provide the patient with accurate prognostic information as well as select appropriate therapy. For example, the presence of either PDGFRA or PDGFRB mutations warrants the use of imatinib in clonal eosinophilia. In HES, prednisone, hydroxyurea, and interferon-α constitute first-line therapy, whereas imatinib, cladribine, and monoclonal antibodies to either interleukin-5 (mepolizumab) or CD52 (alemtuzumab) are considered investigational. Allogeneic transplantation offers a viable treatment option for drug-refractory cases.

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Immunophenotypic normalization of aberrant mast cells accompanies histological remission in imatinib-treated patients with eosinophilia-associated mastocytosis

Cited by 18 publications

References 6 publications

The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders

Modern Diagnosis and Treatment of Primary Eosinophilia

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