The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRalpha is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.

In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. Though the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have been incompletely characterized. To elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated immunophenotypic HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged immunophenotypic human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared with young HSC. Gene expression profiling revealed that aged immunophenotypic human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, developmental potential, and gene expression profile of human HSC are similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process.

Key Points Dehydrated hereditary stomatocytosis is characterized by abnormal RBC morphology but may involve pseudohyperkalemia and perinatal edema. This syndrome is associated with germline mutations in PIEZO1, encoding a transmembrane protein that induces mechanosensitive currents.

Myelodysplastic syndromes (MDS) are a group of disorders characterized by variable cytopenias and ineffective hematopoiesis. Hematopoietic stem cells (HSCs) and myeloid progenitors in MDS have not been extensively characterized. We transplanted purified human HSCs from MDS samples into immunodeficient mice and show that HSCs are the disease-initiating cells in MDS. We identify a recurrent loss of granulocyte-macrophage progenitors (GMPs) in the bone marrow of low risk MDS patients that can distinguish low risk MDS from clinical mimics, thus providing a simple diagnostic tool. The loss of GMPs is likely due to increased apoptosis and increased phagocytosis, the latter due to the up-regulation of cell surface calreticulin, a prophagocytic marker. Blocking calreticulin on low risk MDS myeloid progenitors rescues them from phagocytosis in vitro. However, in the high-risk refractory anemia with excess blasts (RAEB) stages of MDS, the GMP population is increased in frequency compared with normal, and myeloid progenitors evade phagocytosis due to up-regulation of CD47, an antiphagocytic marker. Blocking CD47 leads to the selective phagocytosis of this population. We propose that MDS HSCs compete with normal HSCs in the patients by increasing their frequency at the expense of normal hematopoiesis, that the loss of MDS myeloid progenitors by programmed cell death and programmed cell removal are, in part, responsible for the cytopenias, and that up-regulation of the "don't eat me" signal CD47 on MDS myeloid progenitors is an important transition step leading from low risk MDS to high risk MDS and, possibly, to acute myeloid leukemia.myelodysplasia | blood disorders | aging | monosomy 7 | cancer stem cell T he World Health Organization (WHO) defines myelodysplastic syndromes (MDS) as a heterogeneous group of related clonal diseases characterized by variable cytopenias due to ineffective hematopoiesis and increased risk of progression to acute myeloid leukemia (AML) (1-4). To date, functional and diagnostic evaluations of immature hematopoietic cells in MDS have predominantly relied on unpurified or partially purified bone marrow cells (most frequently CD34 + cells; reviewed in ref. 5), which have limited power to identify cell lineage specific alterations. We have taken advantage of the purification of highly enriched HSCs and committed myeloid progenitors (6-9) via fluorescence activated cell sorting (FACS) to characterize hematopoietic subsets in primary MDS patient bone marrow samples with the goal of increasing the understanding of MDS pathogenesis.Recent fluorescence in situ hybridization (FISH) and gene expression data from purified HSCs from 5q-MDS patients have suggested an HSC origin for MDS (10-13). HSCs from MDS patients (MDS HSCs) are relatively resistant to lenalidomide and decitabine treatment, because even patients with cytogenetic remission, as determined by FISH on peripheral blood cells, can maintain a significant MDS HSC burden (12, 13). Nevertheless, HSCs from MDS patients have not been shown to initiat...

Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-␣ gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management. IntroductionProtean biologic and clinical presentations characterize idiopathic hypereosinophilia (HES). HES is similar to other diseases given the moniker "diagnosis of exclusion," in that limited understanding of the pathogenesis of the disease has hampered therapeutic advances. The demonstration of increased myeloblasts or clonality or the development of either granulocytic sarcoma or acute myeloid leukemia helps clarify the origin of some cases of chronic eosinophilic leukemia. 1 In a subset of patients, hypereosinophilia is related to excessive secretion of eosinophilopoietic cytokines from a clonal population of lymphocytes. 2 The identification of FIP1-like-1-platelet-derived growth factor receptor-␣ (FIP1L1-PDGFRA) in cases of HES/CEL adds to a growing list of activated fusion tyrosine kinases linked to the pathogenesis of chronic myeloproliferative disorders. 3 It is unique, however, because it is the first description of a gain-of-function fusion protein resulting from a cryptic interstitial deletion between genes rather than a reciprocal chromosomal translocation. The FIP1L1-PDGFR␣ fusion protein transforms hematopoietic cells, and its kinase activity is inhibited by imatinib at a cellular 50% inhibitory concentration (IC 50 ) 100-fold lower than BCR-ABL. 3 Acquisition of an imatinib resistance mutation in the adenosine triphosphate (ATP)-binding domain of PDGFRA in a relapsed patient previously responsive to imatinib supports a critical role for FIP1L1-PDGFR␣ in the pathogenesis of disease and demonstrates that FIP1L1-PDGFR␣ is the therapeutic target of imatinib. 3 The identification of t...