Abraham Avigdor

Sheba Medical Center, Gan, Tel Aviv, Israel

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Publications (66)355.4 Total impact

  • G. Rozic · J. Jakubikova · L. Paukov · A. Duek · A. Avigdor · A. Nagler · M. Leiba
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    ABSTRACT: Allogeneic stem-cell transplantation (SCT) is a potentially curative therapy for lymphoid malignancies. Myeloablative conditioning is associated with high non-relapse mortality (NRM). Reduced-intensity condition (RIC) reduces NRM but relapse rate is increased. Novel regimens with intensive anti-malignancy activity but limited toxicity are of benefit. We evaluated outcomes of 144 lymphoma patients given allogeneic SCT with RIC consisting of fludarabine and treosulfan (FT, n=50), intravenous-busulfan (FB2, n=38) or melphalan (FM, n=56). Sixty-nine patients (48%) had chemo-sensitive disease and 75 (52%) had chemo-refractory disease at SCT. The median follow-up is 39 months (4-149). Three-year survival was 67, 74 and 48% after FT, FB2 and FM, in chemo-sensitive disease (P=0.14) and 34, 11 and 17% in chemo-refractory disease, respectively (P=0.08). Three-year NRM was 24, 24 and 54% (P=0.002), whereas relapse mortality was 22, 34 and 18%, respectively (P=0.13). Multivariate analysis identified a high comorbidity-score, chemo-refractory disease and FM as associated with shortened survival. In conclusion, FB2 is associated with low NRM and good results in chemo-sensitive disease, but with higher relapse mortality rates. FM controls disease better, but with high NRM. FT probably balances these outcomes more optimally. It is as safe as FB2 and as cytoreductive as FM, resulting in improved outcome, mostly in advanced disease.Bone Marrow Transplantation advance online publication, 3 August 2015; doi:10.1038/bmt.2015.174.
    Bone marrow transplantation 08/2015; DOI:10.1038/bmt.2015.174 · 3.57 Impact Factor
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    ABSTRACT: A multicenter retrospective analysis of a cohort of patients in Israel treated with any bendamustine containing regimen between 2010 and 2014 was performed in order to determine the incidence and predictors for infection. The Kaplan Meier Model, employing log rank analysis, was used to assess time-to-infection. The Cox Proportional Hazards model was used to analyze multivariate effects of risk and 234 patients were included in the analysis. One hundred and nine (46.6%) developed at least one infection, and 33.76% had severe infections. Seventy six (41.5%) developed bacterial infection, 9 (3.8%) fungal infection and 26 (11.5%) had viral infections. Factors significantly associated with time to infection on multivariable analysis were: bendamustine-combinations [hazard ratio (HR) of 0.589 (95% CI 0.374-0.926), p = 0.022], Hb level [HR 0.791 (95% CI 0.716-0.875), p<0.0001] and ischemic heart disease [HR 1.828 (95% CI 1.165-2.868), p=0.009]. Infections were associated with a higher mortality and hospitalization rate.
    Leukemia & lymphoma 05/2015; DOI:10.3109/10428194.2015.1046862 · 2.89 Impact Factor
  • Meirav Kedmi · Abraham Avigdor · Arnon Nagler
    01/2015; DOI:10.1159/000380931
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    ABSTRACT: Acute myeloid leukemia (AML) relapse is often associated with a poor outcome, especially after allogeneic stem cell transplantation (Allo-SCT). In patients relapsing early after SCT treatment, options are further limited by the fear for increased toxicity. We report our experience with ARA-C and gemtuzumab ozogamicin (GO) combination in relapsed post-SCT AML patients. Therapy consisted of ARA-C (1 gr/m(2)) for 4 days followed by one dose of GO 9 mg/m(2) on day 5 and was supported by donor stem cells when possible. Responding patients not developing graft versus host disease (GVHD) were eligible for immunotherapy with donor lymphocyte infusion (DLI) or a second Allo-SCT. Sixteen patients, median age 53 years (range 31-63), are included in this analysis. Patients underwent SCT for high-risk AML (n = 11) or AML relapse (n = 5), and 81 % had an early post-SCT relapse. Responses were achieved in 60 % of evaluable patients (CR-5 CRp-4). Median probabilities of survival (OS) and event-free survival (EFS) in the entire cohort, responding and non-responding patients were 103 and 76 days, 183 and 97 days, and 79 and 16 days, respectively. At 1-year follow-up, 25 % of patients were alive; however, all had relapse. Treatment resulted in grade 3-4 neutropenia and thrombocytopenia in all patients, and 27 % each had grade 3-4 hyperbilirubinemia or elevation of liver enzymes. One patient died during treatment due to intracranial hemorrhage. Of the six patients proceeding to second SCT or receiving DLI, three patients developed mild veno-occlusive disease (VOD). Combination therapy with ARA-C and GO after SCT results in short-term disease control and limited toxicity and could be considered for patients who are candidates for further immunotherapy.
    Annals of Hematology 10/2014; 94(3). DOI:10.1007/s00277-014-2229-3 · 2.63 Impact Factor
  • Meirav Kedmi · Abraham Avigdor · Arnon Nagler
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    ABSTRACT: Cancer immunotherapy with tumor-directed antibodies has generally been very successful, while T-cell immunotherapy has been less effective. Some lymphoid malignancies can be cured with immunochemotherapy but nevertheless many patients relapse or progress in spite of maximal therapy. Both solid tumors and lymphoid malignancies develop mechanisms in order to escape destruction by the intact immune system. One such mechanism is mediated through immune checkpoints. PD-1 (programmed cell death protein-1, which is expressed on activated T and B cells, natural killer cells and myeloid cells, is one of those checkpoints. This review focuses on the effect of PD-1 activation on lymphoid malignancies and its role as a therapeutic target. © 2014 S. Karger AG, Basel.
    Acta Haematologica 09/2014; 133(2):129-135. DOI:10.1159/000362151 · 1.12 Impact Factor
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    Merav Leiba · Abraham Avigdor
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    ABSTRACT: Keywords:multiple myeloma;induction therapy;bortezomib, thalidomide and dexamethasone;bortezomib, cyclophosphamide and dexamethasone
    British Journal of Haematology 09/2014; 168(4). DOI:10.1111/bjh.13125 · 4.71 Impact Factor
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    ABSTRACT: Three-drug induction regimens have become the standard of care in newly diagnosed transplant-eligible multiple myeloma patients. Two frequently used protocols are bortezomib, cyclophosphamide and dexamethasone (VCD) and bortezomib, thalidomide and dexamethasone (VTD). Comparisons between the two are lacking. The present study aimed to identify the differences in response rate and toxicity between the two regimens. Databases were searched using the terms 'VTD' or 'VCD' and 'induction regimens for newly diagnosed multiple myeloma'. Prospective trials evaluating initial response in transplant eligible patients were included. The main outcome measures were response rates and adverse events. Eight clinical trials were eligible for analysis. Overall 672 patients were treated with either VCD (n = 157) or VTD (n = 515) as induction therapy. Patients treated with VTD presented with a significantly higher complete/near complete response (34% vs. 6%, P = 0·002) as well as a higher very good partial response rate or better, following induction therapy (62% vs. 27%, P < 0·0001). Although grade 3-4 neurotoxicity was more frequent during VTD therapy (11% vs. 6%, P = 0·057), a higher incidence of overall grade 3-4 adverse events was found in the VCD-treated patients (74% vs. 51%, P < 0·001). VTD induction therapy may be superior in achieving deeper response rate following induction therapy, and is better tolerated.
    British Journal of Haematology 05/2014; 166(5). DOI:10.1111/bjh.12946 · 4.71 Impact Factor
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    ABSTRACT: Background: Acute lymphocytic leukemia (ALL) is a rare disease with a poor outcome in adults. Over the years different protocols have been developed with the aim of improving the outcome. The German study group protocols (GMALL), which are the most frequently used in our institutions, changed significantly between the periods 1989-93 and 1999-2003. Objectives: To investigate whether the change in protocols over the years resulted in an outcome difference at two hospitals in Israel. Methods: We thoroughly reviewed the records of 153 patients from Sheba Medical Center and Soroka Medical Center, of whom 106 comprised the study group. The patients were divided into two groups according to the treatment protocol used: 40 patients with the 1989/93 protocol and 66 with the 1999/2003 protocol. Outcome was analyzed for the two groups. Results: We found a significant difference in disease-free survival (DFS) between the two groups for B cell-ALL (B-ALL) patients who achieved complete remission after induction. There was no difference in overall survival. We did not find any difference in outcome for T cell-ALL patients or for CD20-positive patients. Conclusions: In our retrospective analysis, GMALL 99/2003 led to a better DFS for B-ALL patients who were in complete remission after induction. This is possibly related to the differences in medications between the protocols but may also be due to better supportive care. Despite the proven advantage of the newer protocols regarding overall survival, in our experience there was no other significant difference between the two regimens.
    The Israel Medical Association journal: IMAJ 04/2014; 16(4):224-8. · 0.90 Impact Factor
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    ABSTRACT: The choice of a rituximab-based regimen and the prognostic significance of interim 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in primary mediastinal large B cell lymphoma (PMBCL) are debatable. We evaluated the clinical features and outcomes of 95 consecutive patients with PMBCL who were treated between 1985 and 2009. Forty-three patients received rituximab-based chemotherapy, R-VACOP-B (N = 30) or R-CHOP21 (N = 13), whereas 52 patients were treated with VACOP-B (N = 47) or CHOP21 (N = 5). Radiotherapy was not given. Patients who received rituximab had a 5-year progression-free survival (PFS) of 79 % and overall survival (OS) of 97 % compared with 58 % (p = 0.06) and 88 % (p = 0.2), respectively, without rituximab. Five-year PFS in patients treated with R-VACOP-B, R-CHOP21, VACOP-B, and CHOP21 were 83, 69, 62, and 20 %, respectively (p = 0.039). However, direct comparison showed that the difference between PFS rates in patients receiving R-VACOP-B compared to R-CHOP21 was not statistically significant (p = 0.3). None of the standard clinical risk factors predicted for PFS and OS in patients receiving rituximab (R)-chemotherapy. Mid-interim FDG-PET/CT scans were performed in 30/43 patients who received R-chemotherapy. The negative predictive values of mid-PET activity were high (100 % for R-VACOP-B and 86 % for R-CHOP21) while the positive predictive values (PPV) were relatively low (30 and 75 %, respectively). Despite the low PPV, the 5-year PFS for mid-PET-negative patients (N = 16) was significantly higher (94 %) than that for mid-PET-positive (N = 14) patients (57 %, p = 0.015). This retrospective analysis demonstrates that the superiority of VACOP-B over CHOP21 for treatment of PMBCL disappeared once rituximab was added. The potential benefit of using interim PET activity as a guide for continuing therapy in patients with PMBCL remains unclear due to the relatively low PPV.
    Annals of Hematology 03/2014; 93(8). DOI:10.1007/s00277-014-2043-y · 2.63 Impact Factor
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    ABSTRACT: Abstract FDG-PET/CT scanning is often used for staging and response assessment in Mantle cell lymphoma (MCL); however, the ability of interim and post therapy scans to predict outcome is debatable. We retrospectively evaluated the prognostic impact of interim and post therapy FDG-PET/CT scan on outcome of patients with MCL. Fifty eight consecutive patients diagnosed between 1998 and 2011 were included in the analysis. Scans, performed at diagnosis, mid-therapy, post chemotherapy (prior to ASCT) and post transplantation, were reviewed and outcome was analyzed. Median age was 59. Most patients presented with advanced disease. MIPI was low in 45%, intermediate in 41% and high in 14%. Thirty four patients (58%) received RCHOP or RCHOP-like chemotherapy and 24 (42%) underwent an upfront ASCT. Three years overall (OS) and progression free survival (PFS) were 81% and 45% respectively. No significant differences in OS or PFS between the PET positive and PET negative groups both for interim and post therapy scans were observed. Analysis of chemotherapy only and chemotherapy+ASCT groups separately did not reveal any correlation between interim, post therapy or pre transplant PET result to OS and PFS. We conclude that in patients treated with R-CHOP-21 or R-CHOP- like chemotherapy using the International Harmonization Project criteria to determine whether a scan is positive or negative, there is no role for interim or post therapy PET.
    Leukemia & lymphoma 01/2014; DOI:10.3109/10428194.2014.882506 · 2.89 Impact Factor
  • Abraham Avigdor
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    ABSTRACT: In this issue of Blood, Khan and colleagues evaluated the clinical implications of marrow involvement identified by FDG-PET-CT (2-[ 18F]fluoro-2-deoxy-Dglucose- positron emission tomography combined with computed tomography) vs iliac crest biopsy in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). They showed that FDG-PET-CT scanning had a higher level of accuracy for identifying marrow disease than bone marrow (BM) biopsy (BMB). Nevertheless, the identification of BM involvement by histology per se still had a prognostic impact in terms of overall survival (OS) and progression-free survival (PFS).1
    Blood 07/2013; 122(1):4-5. DOI:10.1182/blood-2013-05-502575 · 10.45 Impact Factor
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    ABSTRACT: Purpose: Chemokine axis CXCR4/CXCL12 is critically involved in the survival and trafficking of normal and malignant B lymphocytes. Here, we investigated the effect of high-affinity CXCR4 antagonist BKT140 on lymphoma cell growth and rituximab-induced cytotoxicity in vitro and in vivo. Experimental design: In vitro efficacy of BKT140 alone or in combination with rituximab was determined in non-Hodgkin lymphoma (NHL) cell lines and primary samples from bone marrow aspirates of patients with NHL. In vivo efficacy was evaluated in xenograft models of localized and disseminated NHL with bone marrow involvement. Results: Antagonizing CXCR4 with BKT140 resulted in significant inhibition of CD20+ lymphoma cell growth and in the induction of cell death, respectively. Combination of BKT140 with rituximab significantly enhanced the apoptosis against the lymphoma cells in a dose-dependent manner. Moreover, rituximab induced CXCR4 expression in lymphoma cell lines and primary lymphoma cells, suggesting the possible interaction between CD20 and CXCR4 pathways in NHL. Primary bone marrow stromal cells (BMSC) further increased CXCR4 expression and protected NHL cells from rituximab-induced apoptosis, whereas BKT140 abrogated this protective effect. Furthermore, BKT140 showed efficient antilymphoma activity in vivo in the xenograft model of disseminated NHL with bone marrow involvement. BKT140 treatment inhibited the local tumor progression and significantly reduced the number of NHL cells in the bone marrow. Combined treatment of BKT140 with rituximab further decreased the number of viable lymphoma cells in the bone marrow, achieving 93% reduction. Conclusions: These findings suggest the possible role of CXCR4 in NHL progression and response to rituximab and provide the scientific basis for the development of novel CXCR4-targeted therapies for refractory NHL.
    Clinical Cancer Research 05/2013; 19(13). DOI:10.1158/1078-0432.CCR-12-3015 · 8.72 Impact Factor
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    Biology of Blood and Marrow Transplantation 02/2013; 19(2):S239. DOI:10.1016/j.bbmt.2012.11.305 · 3.40 Impact Factor
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    ABSTRACT: Secondary malignancies are well established complication in long-term survivors after allogeneic stem-cell transplantation (alloSCT) with myeloablative conditioning (MAC). Fludarabine-based reduced-intensity (RIC) and reduced-toxicity (RTC) regimens are increasingly used in the last decade, however, due to limited long-term follow-up, there is no data on secondary malignancies in this setting. The records of 931 consecutive patients given alloSCT with MAC (n=257), RIC (n=449) or RTC (n=225), in a single institution over a 13-year period, were reviewed. Twenty-seven patients had secondary malignancy, diagnosed a median of 43 months (7 months-11.5 years) after SCT. The 10-year cumulative incidence was 5.6% (95%CI, 3.6-8.7), twice the expected rate in matched normal population. The incidence was 1.7, 7.4, and 5.7% after MAC, RIC and RTC, respectively (P=0.02). Multivariate analysis identified fludarabine-based conditioning (HR 3.5, P=0.05), moderate-severe chronic graft-versus-host disease (HR 2.8, P=0.01) and diagnosis of chronic myeloproliferative or non-malignant disease (HR 0.2, P=0.04) as risk-factors for secondary malignancy. The related 10-year mortality rate was 2.4% (95%CI, 1.0-5.4). In conclusion, the risk of secondary malignancies is not reduced and is even possibly increased in the era of fludarabine-based RIC/RTC. Patients and physicians should be aware of this association and life-long cancer screening is required for all transplant survivors.Leukemia accepted article preview online, 17 October 2012; doi:10.1038/leu.2012.299.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2012; 27(4). DOI:10.1038/leu.2012.299 · 10.43 Impact Factor
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    ABSTRACT: High-dose chemotherapy combined with autologous stem-cell transplantation (ASCT) is the standard therapy for refractory/relapsed aggressive lymphoma. In the era of rituximab-containing frontline regimens, it is becoming more challenging to salvage patients in this setting, and novel approaches are required. This is a randomized study evaluating the safety and efficacy of standard-dose ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy (Z-BEAM) and ASCT in refractory/relapsed aggressive lymphoma. Forty-three patients with CD20(+) -aggressive lymphoma were randomized to a treatment arm (Z-BEAM, n = 22) or control arm (BEAM alone, n = 21). Ibritumomab tiuxetan was given at 0.4 mCi/kg on day -14 before ASCT. Patient characteristics, engraftment kinetics, and toxicity profile were similar between the 2 groups. Two-year progression-free survival (PFS) for all patients was 48% (95% confidence interval, 32%-64%): 59% and 37% after Z-BEAM and BEAM alone, respectively (P = .2). Multivariate analysis identified advanced age (hazard ratio [HR], 8.3; P = .001), high-risk disease (relapse within 12 months of diagnosis and/or secondary International Prognostic Index >2; HR, 2.8; P = .04), positive positron emission tomography-computed tomography pretransplant (HR, 2.4; P = .07), and BEAM alone (HR, 2.8; P = .03) as poor prognostic factors. Intermediate-risk patients with 1 or 2 risk factors had better PFS with Z-BEAM compared with BEAM: 69% and 29%, respectively (P = .07). Two-year overall survival was 91% and 62% after Z-BEAM and BEAM, respectively (P = .05). Similar prognostic factors determined survival. The HR for BEAM alone in the multivariate analysis was 8.1 (P = .01). Standard-dose ibritumomab tiuxetan combined with BEAM high-dose chemotherapy is safe and possibly more effective than BEAM alone as a conditioning regimen for ASCT in the era of rituximab-containing chemotherapy regimens. Cancer 2012. © 2012 American Cancer Society.
    Cancer 10/2012; 118(19):4706-14. DOI:10.1002/cncr.27418 · 4.89 Impact Factor
  • Tima Davidson · Elinor Goshen · Abraham Avigdor · Tzila Zwas
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    ABSTRACT: PURPOSE NL is defined as infiltration of nerves by malignant cells of lymphocyte origin presenting as a rare extra-nodal manifestation of lymphoma. About 50% of NL was diagnosed prior to PET-CT development, at autopsy. Yet, even since then only sporadic cases of NL were reported. We present a retrospective study of 9 lymphoma patients group with NL diagnosed by PET/CT either at presentation or upon disease recurrence,at our institution. METHOD AND MATERIALS During 2004-2010 period, 9 patients (age range 23-69); mean 50 yrs, including 5 females and 4 males were evaluated. 7/9 patients had diffuse large B-cell lymphoma (DLBC) and 2/9- Hodgkin’s lymphoma, transformed to DLBC, who underwent PET CT .A whole body PET-CTwas performed 50` post i.v. injection of 10 mCi F-18-FDG, using 16 slices Helical CT (GXL Philips,LTD). Disease staging, treatment monitoring and follow-up was performed .Their PET-CT findings were correlated with clinical findings, other pertinent diagnostic modalities (MRI,US) and clinical follow-up of up to 6 years. RESULTS Most typical NL visualization on 18F-FDG PET-CT scan was a linear shaped uptake pattern along the corresponding thickened nerve tract or neural plexus; or a linear uptake finding simulating the course of a neural tract location. These NL findings were located in extra nodal sites, mostly involving multiple cranial or peripheral nerves, nerve roots at different vertebral levels, or branchial and lumbar plexsuses. These findings frequently accompanyed nodal disease recurrence, necessitating specific attention with early changes in this aggressive disorder management. There were no falsely diagnosed NL results in our group. The appearance of the findings often resembled vascular , lymphatic or muscular tract but anatomic CT localizations aided in identifying their correct nature and locations and as a viable neural disease. CONCLUSION F-l8 FDG PET-CT in our lymphoma group appears to be a highly sensitive and specific in the disgnosis of NL. It has been more frequently diagnosed in recent years, due to increased awareness and extensive use of hybrid PET-CT, enabling anatomic as well as hypermetabolic processes localization in neural structures. Early recognition and treatment of this rare lymphoma manifestation indeed improved disease outcome in our group. CLINICAL RELEVANCE/APPLICATION Early recognition and treatment of NL, a rare lymphoma manifestation, indeed improves disease outcome in lymphoma patients.
    Radiological Society of North America 2011 Scientific Assembly and Annual Meeting; 11/2011
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    ABSTRACT: Bone marrow homing and engraftment by clinically transplanted hematopoietic stem and progenitor cells is a complex process that is not fully understood. We report that the pan-leukocyte CD45 phosphatase plays an essential role in trafficking and repopulation of the bone marrow by immature human CD34(+) cells and leukemic cells in transplanted nonobese diabetic severe combined immunodeficient mice. Inhibiting CD45 function by blocking antibodies or a CD45 inhibitor impaired the motility of both normal and leukemic human cells. Blocking CD45 inhibited homing and repopulation by immature human CD34(+) cells as well as homing of primary patient leukemic cells. In addition, CD45 inhibition negatively affected development of hematopoietic progenitors in vitro and their recovery in transplanted recipients in vivo, revealing the central role of CD45 in the regulation of hematopoiesis. Moreover, CD45 blockage induced a hyperadhesive phenotype in immature human progenitor cells as well as in murine leukocytes, leading to their defective adhesion interactions with endothelial cells. This phenotype was further manifested by the ability of CD45 blockage to prevent breakdown of adhesion interactions in the BM, which inhibited murine progenitor mobilization. The substantial effects of a direct CD45 inhibition point at its essential roles in cell trafficking, including murine progenitor cell mobilization and both normal immature and leukemic human hematopoietic cells as well as regulation of hematopoiesis and engraftment potential.
    Experimental hematology 09/2011; 39(12):1161-1170.e1. DOI:10.1016/j.exphem.2011.08.012 · 2.48 Impact Factor
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    ABSTRACT: Rearrangements of the MLL (ALL1) gene are very common in acute infant and therapy-associated leukemias. The rearrangements underlie the generation of MLL fusion proteins acting as potent oncogenes. Several most consistently up-regulated targets of MLL fusions, MEIS1, HOXA7, HOXA9, and HOXA10 are functionally related and have been implicated in other types of leukemias. Each of the four genes was knocked down separately in the human precursor B-cell leukemic line RS4;11 expressing MLL-AF4. The mutant and control cells were compared for engraftment in NOD/SCID mice. Engraftment of all mutants into the bone marrow (BM) was impaired. Although homing was similar, colonization by the knockdown cells was slowed. Initially, both types of cells were confined to the trabecular area; this was followed by a rapid spread of the WT cells to the compact bone area, contrasted with a significantly slower process for the mutants. In vitro and in vivo BrdU incorporation experiments indicated reduced proliferation of the mutant cells. In addition, the CXCR4/SDF-1 axis was hampered, as evidenced by reduced migration toward an SDF-1 gradient and loss of SDF-1-augmented proliferation in culture. The very similar phenotype shared by all mutant lines implies that all four genes are involved and required for expansion of MLL-AF4 associated leukemic cells in mice, and down-regulation of any of them is not compensated by the others.
    Proceedings of the National Academy of Sciences 05/2011; 108(19):7956-61. DOI:10.1073/pnas.1103154108 · 9.67 Impact Factor

Publication Stats

2k Citations
355.40 Total Impact Points


  • 1999–2015
    • Sheba Medical Center
      • Cancer Research Center
      Gan, Tel Aviv, Israel
  • 2000–2014
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 2011
    • Thomas Jefferson University
      • Division of Hematology
      Philadelphia, Pennsylvania, United States
  • 2004–2011
    • Weizmann Institute of Science
      • Department of Immunology
      Rechovot, Central District, Israel
    • Medical University of Gdansk
      Danzig, Pomeranian Voivodeship, Poland
  • 1998
    • Meir Medical Center
      Kafr Saba, Central District, Israel