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  • 1
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    Correlation of Clinical and Molecular Response to Imatinib in Polycythemia Vera (PV) Patients with Bone Marrow Morphologic and Immunophenotypic Changes.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 4914-4914
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4914-4914
    Abstract: Imatinib, a tyrosine kinase inhibitor, is effective in treating erythrocytosis and splenomegaly in many PV patients (pts), but is less effective controlling thrombocytosis or splenomegaly in others. Imatinib in PV pts may inhibit c-kit signaling, essential for erythroid progenitor proliferation and/or PDGF-R signaling. The JAK2 V617F mutation is present in most PV pts. We found imatinib therapy in PV pts resulted in a modest molecular response based on %V617F that correlated with hematologic improvement/clinical response; however, those who achieved complete hematological remission had initially lower %V617F. Here we correlate bone marrow (BM) morphology and immunophenotype with clinical/molecular response to imatinib in 10 pts fulfilling criteria for PV (8 men, 2 women; 28–72 yr) treated with imatinib (400–800 mg/day) for 5–31 mo. Cytogenetics in 1 pt showed +9; 4 were normal. CR was defined as phlebotomy-free within18 mo. of treatment (Tx), HCT level & lt;45% for men/ & lt;42% for women, platelet count & lt;400×109/L and no splenomegaly. PR was similarly defined except the platelet count & gt; 400×109/L and & lt;50% reduction of palpable spleen size. %JAK2V617F was determined by pyrosequencing on pre-tx BM (5 pts) and post-tx PBL samples (all pts). Morphologic evaluation was done on sequential BM biopsies based on H & E/reticulin/trichrome stains and available BM aspirate smears. IHC was used to identify progenitors (CD34, CD117), megakaryocytes (MK; CD61), erythoid precursors (GlycoC), granulocytic precursors (MPO); MK c-mpl expression; proliferation (Ki-67). 2 pts showed CR, 6 PR and 2 NR. Median %V617F in CR was 15% (range 8–21%), in PR 57% (range 19–83%) and in NR 58% (range 44–72%). Both CR pts had 2–3-fold decrease in %V617F, whereas 3/6 PR pts had an increase (1–1.5 fold) in %V617F on tx. The 2 CR pts had in the pre-tx BM increased cellularity (60–80%), normal M:E ratio, moderate increase in MKs (10–15/20x). Imatinib tx resulted in normalization of cellularity, decreased erythropoiesis, a lesser decrease in granulopoiesis/megakaryopoiesis, and decreased proliferation in 1 pt (57% to 20%); the other the proliferation was stable at 24%. Reticulin fibrosis was minimal/mild. The PR/NR pre-tx BMs had markedly increased cellularity (80–100%), moderate/marked erythroid hyperplasia, increased granulopoiesis and moderate/marked increase in polymorphic MKs (10 to & gt;30/20x). Imatinib Tx resulted in decreased erythroid cells; less granulopoiesis; and no change/increased MKs with clustering and shedding of CD61+ platelets clumps into stroma. 2 cases progressed to fibrosis.The proliferation was variable (15–30%) with no change on Tx. C-mpl expression in MKs decreased with disease progression. The % cells expressing CD34 and/or CD117 was low and did not change. We found BM morphologic and immunophenotypic changes correlate with clinical/molecular response to imatinib in PV pts. Thus, BM evaluation may be helpful in assessing severity/disease progression and identifying pts who may benefit from imatinib Tx. The findings also suggest heterogeneity of hematopoietic stem cell proliferation. Targeting JAK2/other pathways involved in MK proliferation/migration may be beneficial in PV pts with large numbers of MKs who likely progress to fibrosis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.4914.4914
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 2
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    Lymphoma Diagnosis and Plasma Epstein‐Barr Virus Load during Vicriviroc Therapy: Results of the AIDS Clinical Trials Group A5211
    Oxford University Press (OUP) ; 2009
    In:  Clinical Infectious Diseases Vol. 48, No. 5 ( 2009-03), p. 642-649
    Details
    In: Clinical Infectious Diseases, Oxford University Press (OUP), Vol. 48, No. 5 ( 2009-03), p. 642-649
    Type of Medium: Online Resource
    ISSN: 1058-4838 , 1537-6591
    URL: Issue
    URL: Article
    DOI: 10.1086/597768
    DOI: 10.1086/597007
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2009
    detail.hit.zdb_id: 2002229-3
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  • 3
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    The mechanisms underlying MMR deficiency in immunodeficiency‐related non‐Hodgkin lymphomas are different from those in other sporadic microsatellite instable neoplasms
    Wiley ; 2009
    In:  International Journal of Cancer Vol. 125, No. 10 ( 2009-11-15), p. 2360-2366
    Details
    In: International Journal of Cancer, Wiley, Vol. 125, No. 10 ( 2009-11-15), p. 2360-2366
    Abstract: The spectrum of tumors showing microsatellite instability (MSI) has recently been enlarged to sporadic neoplasms whose incidence is favored in the context of chronic immunosuppression. We investigated the biological, therapeutic and clinical features associated with MSI in immunodeficiency‐related non‐Hodgkin lymphomas (ID‐RL). MSI screening was performed in 275 ID‐RL. MSI ID‐RL were further analyzed for MMR gene expression and for BRAF/KRAS mutations since these genes are frequently altered in MSI cancers. We also assessed the expression of O 6 ‐methylguanine‐DNA methyltransferase (MGMT), an enzyme whose inactivation has been reported in lymphomas and may help in the selection of MMR deficient clones. Unlike other sporadic MSI neoplasms, MSI ID‐RL ( N = 17) presented with heterogeneous MMR defects and no MLH1 promoter methylation. About one third of these tumors presented with normal expression of MLH1, MSH2, MSH6 and PMS2 . They accumulated BRAF activating mutations (33%). Unlike other ID‐RL, MSI ID‐RL were primarily EBV‐negative NHL of T‐cell origin, and arose after long‐term immunosuppression in patients who received azathioprine as part of their immunosuppressive regimen ( p = 0.05) and/or who exhibited methylation‐induced loss of expression of MGMT in tumor cells ( p = 0.02). Overall, these results highlight that, in the context of deficient immune status, some MSI neoplasms arise through alternative mechanism when compared to other sporadic MSI neoplasms. They give the exact way how to make the diagnosis of MSI in these tumors and may help to define biological and clinicalrisk factors associated with their emergence in such a clinicalcontext. © 2009 UICC
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v125:10
    DOI: 10.1002/ijc.24681
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2009
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  • 4
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    Phase 1/2 trial of BMS-275291 in patients with human immunodeficiency virus-related Kaposi sarcoma : A multicenter trial of the AIDS Malignancy Consortium
    Wiley ; 2008
    In:  Cancer Vol. 112, No. 5 ( 2008-03), p. 1083-1088
    Details
    In: Cancer, Wiley, Vol. 112, No. 5 ( 2008-03), p. 1083-1088
    Type of Medium: Online Resource
    ISSN: 0008-543X , 1097-0142
    URL: Issue
    URL: Journal
    URL: Article
    DOI: 10.1002/cncr.v112:5
    DOI: 10.1002/(ISSN)1097-0142
    DOI: 10.1002/cncr.23108
    Language: English
    Publisher: Wiley
    Publication Date: 2008
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  • 5
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    Selective Inhibition of CDK4 and CDK6 Primes Chemoresistant MCL Cells for Killing by Proteasome Inhibitor Bortezomib by Activating Cell Cycle-Coupled Apoptosis
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 3624-3624
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3624-3624
    Abstract: Mantle Cell Lymphoma (MCL) remains generally incurable, suggesting that more effective control of unrestrained tumor growth is essential. Loss of cell cycle control is a hallmark of cancer, in particular of MCL where cell cycle progression through G1 is accelerated due to elevation of cyclin-dependent kinase 4 (CDK4) and constitutive cyclin D1 expression. Thus, one rational approach to improve MCL therapy is to target CDK4/6 in combination with cytotoxic killing. Although success in targeting the cell cycle in cancer with broad-spectrum CDK inhibitors has been modest, PD 0332991, the only known CDK4/6-specific inhibitor with oral bioavailability, has been shown to selectively and potently inhibit CDK4/6 in MCL cells ex vivo. Additionally, in a proof-of-mechanism study in patients with recurrent MCL, we have found that PD 0332991 is well tolerated, and effective in inhibiting CDK4 and CDK6 and suppressing tumor growth in vivo. Of note, 50% of the patients (8/16) have achieved a stable disease for greater then 40 weeks (Leonard et al, abstract submitted to ASH 2008). These findings suggest that selective targeting of CDK4 and CDK6 with PD 0332991 is a promising therapy for MCL. To advance targeting of the cell cycle in cancer, we have developed two novel approaches to both inhibit tumor cell proliferation and activate cell cycle-coupled apoptosis in MCL. We show in primary MCL tumor cells and MCL cell lines by BrdU pulse labeling and DNA content analysis that selective inhibition of CDK4/6 with PD 0332991 leads to a complete G1 arrest, despite high level of c-Myc expression and extensive chromosomal abnormality. As PD 0332991 acts reversibly, removal of PD 0332991 immediately releases the G1 block and induces synchronous ( 〉 90%) G1-S cell cycle progression and S phase entry. This sensitizes chemoresistant MCL cells to killing by suboptimal doses of cytotoxic agents such as bortezomib, through activating cell cycle-coupled apoptosis during S phase entry. Synergistic killing of MCL cells by induction of cell cycle synchronization with PD 0332991 in combination with bortezomib is mediated by induction of mitochondrial membrane depolarization and activation of caspase-9. In a complementary study, we have demonstrated that selective targeting of CDK4 and CDK6 by PD 0332991 similarly primes chemoresistant primary myeloma cells for cytotoxic killing by activating cell cycle-coupled apoptosis, and induces synergistic tumor suppression in animal models. Selective targeting of CDK4 and CDK6 by PD 0332991 in combination with cytotoxic killing, therefore, represents a promising new strategy for cell cycle-based therapy for MCL and other hematopoietic malignancies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.3624.3624
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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    detail.hit.zdb_id: 80069-7
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  • 6
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    Lack of PRDM1α Expression in Hodgkin/Reed-Sternberg Cells Is Likely Mediated by a Translational or Post-Translational Mechanism.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 4367-4367
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4367-4367
    Abstract: Hodgkin/Reed Sternberg (H/RS) cells are the neoplastic cells in classical Hodgkin lymphoma (HL). They are thought to resemble post-germinal center (GC) B cells with expression of markers associated with late stage of B-cell differentiation, for example, interferon regulatory factor -4/multiple myeloma-1 (IRF4/MUM1) and syndecan 1 (CD138). The PR (PRDI-BF1-RIZ) domain zinc finger protein 1 (PRDM1), a transcription repressor with a master regulatory role in plasma cell differentiation, is normally co-expressed with IRF-4/MUM-1 in plasma cells and in a subset of activated GC cells committed to plasma cell fate. We studied expression of PRDM1α, the functional isoform of PRDM1, in 14 classical HL cases [including 3 positive for Epstein-Barr-virus (EBV)] and 4 HL cell lines by immunohistochemistry and Western blotting, respectively. H/RS cells in primary HL cases are negative for PRDM1α, implying a desynchrony in expression between IRF-4/MUM1 and PRDM1. While the myeloma cell line U266 expresses relatively abundant PRDM1α, it was undetectable by Western Blotting in all HL cell lines tested, except for the EBV-positive HL cell line L591 which, unlike in vivo H/RS cells, has a Type III EBV latency pattern. PRDM1α expression in L591 but not in vivo H/RS cells suggests that PRDM1 expression may be modulated by latency type-specific EBV-encoded gene products or the B-cell phenotype exhibited by the cell line. The lack of PRDM1α protein in H/RS cells is not due to impaired gene transcription, since real-time quantitative PCR revealed similarly abundant PRDM1α transcripts in the HL cell lines as U266. In the absence of mutation in the PRDM1 coding region, these results suggest that failure to accumulate PRDM1α protein in H/RS cells is likely due to abnormal translation repression or protein turnover. Loss of functional PRDM1 as a result of translational or post-translational deregulation may represent a novel molecular lesion in HL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.4367.4367
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 7
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    Mucosal Epithelial Cells Initiate Frontline Immunoglobulin Class Switching through an SLPI-Regulated Pathway.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 3898-3898
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3898-3898
    Abstract: Introduction. Class switching from IgM to IgG and IgA is central to immunity against microbes and usually occurs in draining lymph nodes and requires activation of B cells by CD4+ T cells expressing CD40 ligand. Growing evidence indicates that B cells can mount frontline IgG and IgA responses at mucosal sites of entry through an alternative CD40-independent pathway involving B cell-activating factor of the TNF family (BAFF, also known as BLyS) and a proliferation-inducing ligand (APRIL). These innate factors are usually produced by dendritic cells and stimulate B cells through at least three distinct receptors. Together with dendritic cells, epithelial cells have a key position at the host-environment interface. Therefore, we asked whether epithelial cells play a role in frontline antibody production. Methods. Tonsillar tissue sections from healthy donors were analyzed for expression of activation-induced cytidine deaminase (AID) by immunohistochemistry and in situ hybridization. A simplified in vitro model reproducing the geometry of mucosal surfaces was used to evaluate the role of epithelial cells in class switching. Briefly, primary epithelial cells and B cells were cultured in the upper and lower chambers, respectively, of a trans-well system. Monocyte-derived dendritic cells were positioned on a filter separating the two chambers. Various microbial product analogues were used to mimic infection. RNA interference was performed to knockdown BAFF in epithelial cells. AID expression, CSR, antibody production and signaling were evaluated in B cells as reported (Litinsky et al., Nat. Immunol.2002, 3:822–829; Qiao et al., Nat. Immunol.2006, 7:302–310). Results. We found that the upper respiratory mucosa of healthy subjects comprised intraepithelial pockets filled with B cells expressing AID, a DNA-editing enzyme associated with ongoing class switch DNA recombination (CSR). Epithelial cells released innate class switch-inducing factors, including BAFF, after sensing microbial products through TLRs, thereby inducing AID expression, CSR, and ultimately IgG and IgA production in neighboring B cells. Epithelial cell-induced antibodies comprised polyreactive IgG and IgA capable of recognizing multiple microbial determinants. Intraepithelial class switching was enhanced by thymic stromal lymphopoietin (TSLP), an epithelial IL-7-like cytokine that augments the innate B cell-licensing functions of dendritic cells, and restrained by secretory leukocyte protease inhibitor (SLPI), an epithelial alarm antiprotease that suppresses AID expression in activated B cells. Conclusions. The present findings indicate that epithelial cells function as non-immune sentinels capable to autonomously orchestrate compartmentalized IgG and IgA responses at the interface between host and environment. This implies that mucosal vaccines should activate both epithelial and immune cells to elicit optimal antibody production.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.3898.3898
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    Neither Germinal Center (GC) vs Non-Germinal Center (Non-GC) Phenotype nor FOXP1 Expression Correlate with Outcome in AIDS-Associated Diffuse Large B-Cell Lymphoma (DLBCL): Study of Patients from AIDS Malignancies Consortium Trials 010 and 034.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-01), p. 2023-2023
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2023-2023
    Abstract: Background: Germinal center (GC) and non-germinal center (non-GC) gene expression profiles correlate with survival in immunocompetent DLBCL patients. Phenotypic expression patterns of CD10, BCL6, MUM1 and CD138 are surrogates for genetic studies with comparable survival data; CD10+, BCL6+/−, MUM1- defines GC while CD10-, BCL6-, MUM1+/− identifies the non-GC phenotype with poorer prognosis. Expression of FOXP1, a transcription factor differentially expressed in resting and activated B cells, and PRDM1/BLIMP1, a regulator of terminal B cell differentiation, are also adverse prognostic markers for DLBCL in immunocompetent patients. AIDS-associated DLBCLs from uniformly treated HIV+ patients in AMC010 (CHOP vs. CHOP-rituxan) and AMC034 (EPOCH vs. EPOCH-rituxan) were examined to determine if the GC vs. non-GC phenotype, FOXP1 expression and/or BLIMP1 expression are prognostic in this patient population. Design: Slides of 32 and 30 AIDS-associated DLBCLs from AMC010 (closed) and AMC034 (in analysis) patients, respectively, were available for FOXP1, BLIMP1, CD10, BCL6, MUM1, BCL2, Ki-67 immunohistochemistry and in situ hybridization for EBV (EBER). Antigen expression by 〉 20% tumor cells ( 〉 10% for BLIMP1) was considered positive. GC phenotype was defined as CD10+, BCL6+/−, MUM1- while the non-GC cases were CD10-, BCL6-, MUM1+/−. Overall survival (OS) based on GC vs. non-GC phenotype was examined. FOXP1 expression was correlated with survival; BCL2, Ki-67 expression; and EBV status; BLIMP1 expression was correlated with survival in a subgroup of patients from AMC 034. Results: Of the 62 cases, 59% were MUM1, 60% BCL6, 53% CD10, 59% BCL2, 49% FOXP1, 67% BLIMP1 and 30% EBER positive. 19 (58%) cases were classified as GC and 14 as non-GC. No mean OS difference between GC and non-GC groups (p=0.74) or FOXP1+ and FOXP1- cases (p=0.8; t-test) in the AMC 010 patients; BLIMP1 expression did not correlate with survival in the subgroup of AMC 034 patients (p=0.4). GC vs. non-GC phenotype did not correlate with FOXP1 expression (p=0.1) or BLIMP1 expression (p=0.4). In addition, FOXP1 expression did not correlate with EBV positivity, BCL2, MUM1, BCL6 or CD10 expression or proliferation rate based on Ki67 (chi-square). Conclusions: AIDS-associated DLBCLs can be classified as GC and non-GC cases, but this classification does not appear to correlate with prognosis/OS in uniformly treated HIV-positive patients. Furthermore, in contrast with immunocompetent DLBCLs, FOXP1 expression also does not correlate with OS in this patient population; similarly BLIMP1 expression also does not correlate with survival in the HIV+ patient population. In addition, GC vs non-GC phenotype did not correlate with FOXP1 or BLIMP1 expression, while FOXP1 expression did not correlate with prognostic markers BCL2/Ki67 or EBV status. Thus, prognostic markers useful in immunocompetent patients with DLBCL may not be relevant for HIV positive patients, suggesting that patient immune status rather than tumor biology may be more important in predicting patient outcome.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2023.2023
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
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    Value of FDG-PET in Prediction of Splenectomy Findings in Patients with Suspected or Known Lymphoma.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-01), p. 2405-2405
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2405-2405
    Abstract: Splenectomy is frequently performed for diagnostic purposes in patients with suspected or known lymphoma, including assessment for possible transformation. The ability to predict splenectomy findings (and potentially avoid associated morbidity and mortality) would be valuable. The purpose of this study was to determine whether preoperative18F-fluorodeoxyglucose positron emission tomography (FDG-PET) results correlate with pathologic diagnosis from splenectomy. Methods: One hundred sixty-five patients who had undergone a splenectomy at New York Presbyterian Hospital from January 2004 to July 2006 were identified from the pathology database. Records of these patients were searched and 11 with suspected or known lymphoma as an indication for splenectomy and who had a pre-splenectomy PET scan were identified. A nuclear medicine physician performed a blinded review and assigned each PET scan to one of the following categories based on splenic FDG standardized uptake values (SUV): low splenic metabolic activity (correlated with maximum SUV range 2-3.7), intermediate splenic metabolic activity (maximum SUV range 6–7), and high splenic metabolic activity (maximum SUV range 26–29). Findings were correlated with splenectomy pathologic diagnosis. Results: Subjects (n=11, 4 female, 7 male) had a median age of 48 years (range 21–72); four had suspected lymphoma pre-splenectomy, while 7 had a prior diagnosis and had splenectomy for diagnostic (to rule out transformation) or other purposes. Median time between PET and splenectomy was 1.25 months. Of 5 patients with low metabolic activity on PET; three had benign findings at splenectomy and two had splenic involvement of previously known mantle cell lymphoma. Three patients had intermediate metabolic activity on PET; all subsequently demonstrated marginal zone lymphoma at splenectomy. Three patients had high metabolic activity on PET; all were found to have diffuse large B cell lymphoma at splenectomy. Conclusions: This study to our knowledge comprises the largest series to evaluate splenic FDG-PET uptake in patients with suspected or known lymphoma, followed by subsequent pathologic confirmation. Patients with low splenic SUVs appear to be less likely to have splenic involvement of lymphoma, while intermediate and high values may correlate with lymphoma histology. Our findings support a potential role for FDG-PET as a tool for use, in conjunction with clinical and laboratory assessment, in consideration of the need for splenectomy in these settings.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2405.2405
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 3 ( 2008-08-01), p. 875-885
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 3 ( 2008-08-01), p. 875-885
    Abstract: In β-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by β-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle–promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-XL. The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2007-12-126938
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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