Publications by authors named "Shai Izraeli"

139 Publications

Metabolic adaptation of acute lymphoblastic leukemia to the central nervous system microenvironment is dependent on Stearoyl CoA desaturase.

Nat Cancer 2020 Oct 28;1(10):998-1009. Epub 2020 Sep 28.

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Metabolic reprogramming is a key hallmark of cancer, but less is known about metabolic plasticity of the same tumor at different sites. Here, we investigated the metabolic adaptation of leukemia in two different microenvironments, the bone marrow and the central nervous system (CNS). We identified a metabolic signature of fatty-acid synthesis in CNS leukemia, highlighting Stearoyl-CoA desaturase () as a key player. SCD1 overexpression increases CNS disease, whilst genetic or pharmacological inhibition of SCD1 decreases CNS load. Overall, we demonstrated that leukemic cells dynamically rewire metabolic pathways to suit local conditions and that targeting these adaptations can be exploited therapeutically.
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http://dx.doi.org/10.1038/s43018-020-00115-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116605PMC
October 2020

DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3.

J Clin Invest 2021 Jan;131(1)

Department of Medicine, Division of Hematology/Oncology, Northwestern University, Chicago, Illinois, USA.

DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer's disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL.
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http://dx.doi.org/10.1172/JCI135937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773384PMC
January 2021

Incorporation of somatic panels for the detection of haematopoietic transformation in children and young adults with leukaemia predisposition syndromes and with acquired cytopenias.

Br J Haematol 2020 Dec 27. Epub 2020 Dec 27.

Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel.

Detection of somatic mutations may help verify the diagnosis of myelodysplastic syndrome (MDS) in patients with persistent cytopenias or with MDS-predisposition syndromes, prior to the development of overt leukemia. However, the spectrum and consequences of acquired changes in paediatric patients have not been fully evaluated, and especially not in the context of an underlying syndrome. We incorporated a targeted next-generation-sequencing panel of 54 genes for the detection of somatic mutations in paediatric and young adult patients with inherited or acquired cytopenias. Sixty-five patients were included in this study, of whom 17 (26%) had somatic mutations. We detected somatic mutations in 20% of individuals with inherited MDS-predisposition syndromes, including in patients with severe congenital neutropenia and Fanconi anaemia, and with germline mutations in SAMD9L. Thirty-eight per cent of children with acquired cytopenias and suspected MDS had somatic changes, most commonly in genes related to signal transduction and transcription. Molecularly abnormal clones often preceded cytogenetic changes. Thus, routine performance of somatic panels can establish the diagnosis of MDS and determine the optimal timing of haematopoietic stem cell transplantation, prior to the development of leukaemia. In addition, performing somatic panels in patients with inherited MDS-predisposition syndromes may reveal their unique spectrum of acquired mutations.
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http://dx.doi.org/10.1111/bjh.17285DOI Listing
December 2020

Venous Thromboembolism and Its Risk Factors in Children with Acute Lymphoblastic Leukemia in Israel: A Population-Based Study.

Cancers (Basel) 2020 Sep 25;12(10). Epub 2020 Sep 25.

Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva 49202, Israel.

Venous thromboembolism (VTE) is a serious complication of acute lymphoblastic leukemia (ALL) therapy. The aim of this population-based study was to evaluate the rate, risk factors, and long-term sequelae of VTE in children treated for ALL. The cohort included 1191 children aged 1-19 years diagnosed with ALL between 2003-2018, prospectively enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. VTEs occurred in 89 patients (7.5%). Long-term sequelae were uncommon. By univariate analysis, we identified four significant risk factors for VTEs: Severe hypertriglyceridemia ( = 0.005), inherited thrombophilia ( < 0.001), age >10 years ( = 0.015), and high-risk ALL group ( = 0.039). In addition, the incidence of VTE was significantly higher in patients enrolled in AIEOP-BFM ALL 2009 than in those enrolled in ALL-IC BFM 2002 ( = 0.001). Severe VTE occurred in 24 children (2%), all of whom had at least one risk factor. Elevated triglyceride levels at diagnosis did not predict hypertriglyceridemia during therapy. In a multivariate analysis of 388 children, severe hypertriglyceridemia and inherited thrombophilia were independent risk factors for VTE. Routine evaluation for these risk factors in children treated for ALL may help identify candidates for intervention.
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http://dx.doi.org/10.3390/cancers12102759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600511PMC
September 2020

COVID-19 - Impact on Childhood Haematology Patients.

Hemasphere 2020 Oct 11;4(5):e465. Epub 2020 Sep 11.

Department of Pediatric Hemato-oncology, Princess Máxima Centrum for Pediatric Oncology, Utrecht, The Netherlands.

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http://dx.doi.org/10.1097/HS9.0000000000000465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489725PMC
October 2020

Signalling input from divergent pathways subverts B cell transformation.

Nature 2020 07 22;583(7818):845-851. Epub 2020 Jul 22.

Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA.

Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5) or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK). STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.
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http://dx.doi.org/10.1038/s41586-020-2513-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394729PMC
July 2020

Predicting brain metastasis in early stage non-small cell lung cancer patients by gene expression profiling.

Transl Lung Cancer Res 2020 Jun;9(3):682-692

Institute of Oncology, Sheba Medical Center, Tel Hashomer, Israel.

Background: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-death due to early metastatic spread, in many cases primarily to the brain. Organ-specific pattern of spread of disease might be driven by the activity of a specific signaling pathway within the primary tumors. We aimed to identify an expression signature of genes and the relevant signaling associated with the development of brain metastasis (BM) after surgical resection of NSCLC.

Methods: Rapidly frozen NSCLC surgical specimens were procured from tumor banks. RNA was extracted and analyzed by RNA-sequencing (Illumina HiSeq 2500). Clinical parameters and gene expression were examined for differentiating between patients with BM, patients with metastases to sites other than brain, and patients who did not develop metastatic disease at a clinically significant follow up. Principal component analysis and pathway enrichments studies were done.

Results: A total of 91 patients were included in this study, 32 of which developed BM. Stage of disease at diagnosis (P=0.004) and level of differentiation (P=0.007) were significantly different between BM and control group. We identified a set of 22 genes which correlated specifically with BM, and not with metastasis to other sites. This set achieved 93.4% accuracy (95% CI: 86.2-97.5%), 96.6% specificity and 87.5% sensitivity of correctly identifying BM patients in a leave-one-out internal validation analysis. The oxidative phosphorylation pathway was strongly correlated with BM risk.

Conclusions: Expression level of a small set of genes from primary tumors was found to predict BM development, distinctly from metastasis to other organs. These genes and the correlated oxidative phosphorylation pathway require further validation as potentially clinically useful predictors of BM and possibly as novel therapeutic targets for BM prevention.
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http://dx.doi.org/10.21037/tlcr-19-477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354143PMC
June 2020

Correction: Exclusive destruction of mitotic spindles in human cancer cells.

Oncotarget 2020 Apr 7;11(14):1290-1291. Epub 2020 Apr 7.

The Neufeld Cardiac Research Institute, Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.

[This corrects the article DOI: 10.18632/oncotarget.15343.].
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http://dx.doi.org/10.18632/oncotarget.27499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147084PMC
April 2020

RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML.

Blood Adv 2020 03;4(6):1131-1144

Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.

First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.
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http://dx.doi.org/10.1182/bloodadvances.2019000901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094007PMC
March 2020

It takes a village to grow leukemia.

Blood 2020 03;135(12):886-887

Schneider Children's Medical Center of Israel.

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http://dx.doi.org/10.1182/blood.2020004990DOI Listing
March 2020

Mucormycosis in children with haematological malignancies is a salvageable disease: a report from the Israeli Study Group of Childhood Leukemia.

Br J Haematol 2020 04 29;189(2):339-350. Epub 2019 Dec 29.

The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, Israel.

Mucormycosis has emerged as an increasingly important cause of morbidity and mortality in immunocompromised patients, but contemporary data in children are lacking. We conducted a nationwide multicentre study to investigate the characteristics of mucormycosis in children with haematological malignancies. The cohort included 39 children with mucormycosis: 25 of 1136 children (incidence 2·2%) with acute leukaemias prospectively enrolled in a centralized clinical registry in 2004-2017, and an additional 14 children with haematological malignancies identified by retrospective search of the databases of seven paediatric haematology centres. Ninety-two percent of mucormycosis cases occurred in patients with acute leukaemias. Mucormycosis was significantly associated with high-risk acute lymphoblastic leukaemia (OR 3·75; 95% CI 1·51-9·37; P = 0·004) and with increasing age (OR 3·58; 95% CI 1·24-9·77; P = 0·01). Fifteen patients (38%) died of mucormycosis. Rhinocerebral pattern was independently associated with improved 12-week survival (OR 9·43; 95% CI 1·47-60·66; P = 0·02) and relapsed underlying malignancy was associated with increased 12-week mortality (OR 6·42; 95% CI, 1·01-40·94; P = 0·05). In patients receiving frontline therapy for their malignancy (n = 24), one-year cumulative mucormycosis-related mortality was 21 ± 8% and five-year overall survival was 70 ± 8%. This largest paediatric population-based study of mucormycosis demonstrates that children receiving frontline therapy for their haematological malignancy are often salvageable.
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http://dx.doi.org/10.1111/bjh.16329DOI Listing
April 2020

Genes driving bad luck.

Blood 2019 10;134(15):1199-1200

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http://dx.doi.org/10.1182/blood.2019002619DOI Listing
October 2019

Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols.

Haematologica 2020 Jul 10;105(7):1887-1894. Epub 2019 Oct 10.

Clinica Pediatrica and Centro Ricerca Tettamanti, Università di Milano-Bicocca, Fondazione MBBM/S.Gerardo Hospital, Monza, Italy.

ABL-class fusions other than characterize around 2-3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of ≥5×10 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases, the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality (TRM) 20.8+6.8%. One out of 13 cases with TKI added to chemotherapy relapsed while eight of 33 cases without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: .
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http://dx.doi.org/10.3324/haematol.2019.231720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327633PMC
July 2020

Poorer outcome of childhood acute lymphoblastic leukemia in the Bedouin population: A report from the Berlin-Frankfurt-Muenster-based Israeli national protocols.

Pediatr Blood Cancer 2020 01 8;67(1):e28024. Epub 2019 Oct 8.

Division of Pediatric Hematology/Oncology, Schneider Children's Medical Center of Israel, Petah Tiqwa, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Therapy outcomes for childhood acute lymphoblastic leukemia (ALL) had substantially improved in the last decades, but variability across racial and ethnic groups was identified in some clinical studies. In this study, we aimed to investigate whether such a difference in outcome is found in the diverse ethnicities in Israel as well.

Methods: A retrospective study was conducted among 1154 patients (855 Jews, 195 Muslims, 52 Bedouins, 26 Druze, and 26 others) aged 1 to 21 years, who were diagnosed with ALL between 1989 and 2011 and were treated according to the same Berlin-Frankfurt-Muenster-based Israel National Study protocols.

Results: Bedouins had a higher incidence of t(1;19) (16% vs 3% for non-Bedouins) and a lower incidence of high-hyperdiploidy (10% vs 25% for non-Bedouins) (P = 0.01). Five-year event-free survival (EFS) and overall survival (OS) were poorer for the Bedouins (60.3% ± 7.2% and 63.1% ± 7.2%, respectively) compared with the Jews, Muslims, and Druze (80.4% ± 1.4%, 77.3% ± 3.2%, and 84% ± 7.3%, respectively, for EFS [P = 0.02], and 86.3% ± 1.2%, 82.3% ± 2.9%, and 88.3% ± 6.4%, respectively, for OS [P = 0.002]). Adherence to intensive chemotherapy was similar between the Muslims and the Bedouins.

Conclusions: Our findings suggest that the Bedouins, a highly inbred ethnic Arab people, may be considered a higher risk group that may need more intensive chemotherapy and/or supportive care in order to improve their outcome.
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http://dx.doi.org/10.1002/pbc.28024DOI Listing
January 2020

The preleukemic TCF3-PBX1 gene fusion can be generated in utero and is present in ≈0.6% of healthy newborns.

Blood 2019 10;134(16):1355-1358

Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

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http://dx.doi.org/10.1182/blood.2019002215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005361PMC
October 2019

Chromatin occupancy and epigenetic analysis reveal new insights into the function of the GATA1 N terminus in erythropoiesis.

Blood 2019 11;134(19):1619-1631

Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL.

Mutations in GATA1, which lead to expression of the GATA1s isoform that lacks the GATA1 N terminus, are seen in patients with Diamond-Blackfan anemia (DBA). In our efforts to better understand the connection between GATA1s and DBA, we comprehensively studied erythropoiesis in Gata1s mice. Defects in yolks sac and fetal liver hematopoiesis included impaired terminal maturation and reduced numbers of erythroid progenitors. RNA-sequencing revealed that both erythroid and megakaryocytic gene expression patterns were altered by the loss of the N terminus, including aberrant upregulation of Gata2 and Runx1. Dysregulation of global H3K27 methylation was found in the erythroid progenitors upon loss of N terminus of GATA1. Chromatin-binding assays revealed that, despite similar occupancy of GATA1 and GATA1s, there was a striking reduction of H3K27me3 at regulatory elements of the Gata2 and Runx1 genes. Consistent with the observation that overexpression of GATA2 has been reported to impair erythropoiesis, we found that haploinsufficiency of Gata2 rescued the erythroid defects of Gata1s fetuses. Together, our integrated genomic analysis of transcriptomic and epigenetic signatures reveals that, Gata1 mice provide novel insights into the role of the N terminus of GATA1 in transcriptional regulation and red blood cell maturation which may potentially be useful for DBA patients.
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http://dx.doi.org/10.1182/blood.2019001234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871310PMC
November 2019

Mechanisms of Leukemia Evolution: Lessons from a Congenital Syndrome.

Cancer Cell 2019 08;36(2):115-117

Division of Pediatric Hematology and Oncology, Schneider Children's Medical Center of Israel, Petach Tikva 49100, Israel; Sackler Medical School, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel. Electronic address:

Studies of the mechanisms of acute leukemia transformation from a preleukemic state in humans are hampered by the absence of clinical preleukemia syndromes. In this issue of Cancer Cell, Labuhn et al. provide a functional genomics view on the leukemic evolution from congenital preleukemia in children with Down syndrome.
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http://dx.doi.org/10.1016/j.ccell.2019.07.004DOI Listing
August 2019

Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B-cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia.

Pediatr Blood Cancer 2019 10 2;66(10):e27898. Epub 2019 Jul 2.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Tremendous progress in the therapy of pediatric acute lymphoblastic leukemia (ALL) has been achieved through combination cytotoxic chemotherapy, leading to high cure rates, at the cost of significant life-threatening toxicity. The bispecific T-cell engager blinatumomab, recently approved for relapsed/refractory ALL, has a unique nonmyelotoxic toxicity profile. As blinatumomab causes B-cell depletion, the safety of its use during severe chemotherapy-induced toxicity is unclear. We report 11 pediatric patients with ALL, treated with blinatumomab following overwhelming chemotherapy-associated toxicity, with recovery of all patients and successful bridging to further antileukemia therapy. Blinatumomab can be considered for rare patients who cannot tolerate cytotoxic therapy.
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http://dx.doi.org/10.1002/pbc.27898DOI Listing
October 2019

An Enhancer-Based Reporter Identifies Leukemia Cells with Elevated Leukemogenic Potential Driven by ERG-USP9X Feed-Forward Regulation.

Cancer Res 2019 08 7;79(15):3862-3876. Epub 2019 Jun 7.

Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Acute leukemia is a rapidly progressing blood cancer with low survival rates. Unfavorable prognosis is attributed to insufficiently characterized subpopulations of leukemia stem cells (LSC) that drive chemoresistance and leukemia relapse. Here we utilized a genetic reporter that assesses stemness to enrich and functionally characterize LSCs. We observed heterogeneous activity of the enhancer-based fluorescent reporter in human leukemias. Cells with high reporter activity (tagBFP) exhibited elevated expression of stemness and chemoresistance genes and demonstrated increased clonogenicity and resistance to chemo- and radiotherapy as compared with their tagBFP counterparts. The tagBFP fraction was capable of regenerating the original cellular heterogeneity and demonstrated increased invasive ability. Moreover, the tagBFP fraction was enriched for leukemia-initiating cells in a xenograft assay. We identified the ubiquitin hydrolase USP9X as a novel ERG transcriptional target that sustains ERG+85-positive cells by controlling ERG ubiquitination. Therapeutic targeting of USP9X led to preferential inhibition of the ERG-dependent leukemias. Collectively, these results characterize human leukemia cell functional heterogeneity and suggest that targeting ERG via USP9X inhibition may be a potential treatment strategy in patients with leukemia. SIGNIFICANCE: This study couples a novel experimental tool with state-of-the-art approaches to delineate molecular mechanisms underlying stem cell-related characteristics in leukemia cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3215DOI Listing
August 2019

JAK2 p.G571S in B-cell precursor acute lymphoblastic leukemia: a synergizing germline susceptibility.

Leukemia 2019 09 9;33(9):2331-2335. Epub 2019 Apr 9.

Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany.

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http://dx.doi.org/10.1038/s41375-019-0459-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756027PMC
September 2019

Need for new thinking: Treatment of relapsed leukemia in children with Down syndrome.

Pediatr Blood Cancer 2019 06 5;66(6):e27644. Epub 2019 Feb 5.

Division of Hematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/pbc.27644DOI Listing
June 2019

A novel method for detecting the cellular stemness state in normal and leukemic human hematopoietic cells can predict disease outcome and drug sensitivity.

Leukemia 2019 08 31;33(8):2061-2077. Epub 2019 Jan 31.

Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel.

Acute leukemia is an aggressive blood malignancy with low survival rates. A high expression of stem-like programs in leukemias predicts poor prognosis and is assumed to act in an aberrant fashion in the phenotypically heterogeneous leukemia stem cell (LSC) population. A lack of suitable genome engineering tools that can isolate LSCs based on their stemness precludes their comprehensive examination and full characterization. We hypothesized that tagging endogenous stemness-regulatory regions could generate a genome reporter for the putative leukemia stemness-state. Our analysis revealed that the ERG  + 85 enhancer region can serve as a marker for stemness-state and a fluorescent lentiviral reporter was developed that can accurately recapitulate the endogenous activity. Using our novel reporter, we revealed cellular heterogeneity in several leukemia cell lines and patient-derived samples. Alterations in reporter activity were associated with transcriptomic and functional changes that were closely related to the hematopoietic stem cell (HSC) identity. Notably, the differentiation potential was skewed towards the erythro-megakaryocytic lineage. Moreover, an ERG  + 85 fraction of AML cells could regenerate the original cellular heterogeneity and was enriched for LSCs. RNA-seq analysis coupled with in silico drug-screen analysis identified 4HPR as an effective inhibitor of ERG  + 85 leukemia growth. We propose that further utilization of our novel molecular tool will identify crucial determinants of LSCs, thus providing a rationale for their therapeutic targeting.
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http://dx.doi.org/10.1038/s41375-019-0386-zDOI Listing
August 2019

Thrombophilia screening and thromboprophylaxis may benefit specific ethnic subgroups with paediatric acute lymphoblastic leukaemia.

Br J Haematol 2019 03 10;184(6):994-998. Epub 2019 Jan 10.

Department of Paediatric Haematology and Oncology, Schneider Children's Medical Centre of Israel, Petach Tivka, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

This study investigated the prevalence of inherited thrombophilia, risk of venous thromboembolism (VTE) and benefit of low molecular weight heparin prophylaxis in 476 Israeli children with acute lymphoblastic leukaemia (ALL) treated between 2004 and 2016. Thrombophilia was found in 15·5%. Arab children had a higher prevalence of F5 R506Q (factor V Leiden) than Jewish children (19·4% vs. 2·9%, P < 0·01). Patients with thrombophilia had higher VTE rates VTE (26·5% vs. 5·6%, P < 0·001). None of the thrombophilic children given prophylaxis had severe VTE. Routine evaluation for inherited thrombophilia followed by thromboprophylaxis when findings are positive may benefit at-risk patients with ALL.
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http://dx.doi.org/10.1111/bjh.15752DOI Listing
March 2019

American Funding Cutback to East Jerusalem Hospitals: A Blow to the Health of the City.

Am J Public Health 2018 12;108(12):1624-1625

A. Mark Clarfield, Shimon M. Glick, and Rivka Carmi are with the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-shev, Israel. Karl Skorecki, Rafi Beyar, Ziv Gil, Salem Billan, Zaher Azzam, and Fuad Basis are with Technion-Israel Institute of Technology, Haifa. Ora Paltiel is with the Department of Hematology, Hadassah-Hebrew University, Jerusalem, Israel. Dina Ben Yehuda is with the Hematology Department, Hadassah Medical Center, Jerusalem. Ephrat Levy-Lahad, Dan Turner, and Yonatan Halevy are with the Shaare Zedek Medical Center, Hebrew University of Jerusalem. Amnon Lahad is with the Department of Family Medicine, Hebrew University of Jerusalem. Shai Izraeli is with the Rina Zaizov Pediatric Hematology Oncology Division, Schneider Children's Medical Center of Israel, Petach Tiqva.

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http://dx.doi.org/10.2105/AJPH.2018.304792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236734PMC
December 2018

Genomic precision medicine: on the TRK.

Blood 2018 08;132(8):773-774

Schneider Children's Medical Center of Israel.

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http://dx.doi.org/10.1182/blood-2018-06-857540DOI Listing
August 2018

International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia.

Blood 2018 07 2;132(3):264-276. Epub 2018 May 2.

Department of Pediatric Hematology/Oncology, Charles University, Second Faculty of Medicine, Hospital Motol, Prague, Czech Republic.

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)-type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19 leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19 ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19 and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial.
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http://dx.doi.org/10.1182/blood-2017-12-821363DOI Listing
July 2018

IKZF1 Defines a New Minimal Residual Disease-Dependent Very-Poor Prognostic Profile in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia.

J Clin Oncol 2018 04 2;36(12):1240-1249. Epub 2018 Mar 2.

Martin Stanulla, Elif Dagdan, Stefanie V. Junk, Laura Hinze, Norman Klein, Christian P. Kratz, Petra Dörge, Doris Steinemann, and Martin Zimmermann, Hannover Medical School; Petra Dörge, German Center for Infection Research, Hannover; Anja Möricke, Kirsten Bleckmann, Denis Schewe, Gunnar Cario, and Martin Schrappe, University Hospital Schleswig-Holstein; Britt-Sabina Petersen and Andre Franke, Kiel University, Kiel; Cornelia Eckert and Stefanie Groeneveld-Krentz, Charité University Hospital; Wolf-Dieter Ludwig, HELIOS-Clinic Berlin-Buch, Berlin; Rolf Koehler, Claus R. Bartram, Andreas Kulozik, and Martina U. Muckenthaler, University of Heidelberg, Heidelberg; Arndt Borkhardt, Heinrich-Heine University, Düsseldorf, Germany; Marketa Zaliova, Charles University and University Hospital Motol, Prague, Czech Republic; Chiara Palmi, Giovanni Cazzaniga, and Andrea Biondi, Azienda Ospedaliera San Gerardo; Maria Grazia Valsecchi, University of Milano-Bicocca, Monza; Geertruy te Kronnie and Giuseppe Basso, University of Padova, Padua, Italy; Jean-Pierre Bourquin and Beat Bornhauser, University Children's Hospital Zurich, Zurich, Switzerland; Shai Izraeli, Sheba Medical Center Tel-Hashomer and Tel Aviv University, Tel Aviv, Israel; Oskar A. Haas and Renate Panzer-Grümayer, St Anna Kinderkrebsforschung and Medical University Vienna, Vienna, Austria; Hélène Cavé, Robert Debré Hospital and Paris-Diderot University, Paris, France; and Richard S. Houlston, The Institute of Cancer Research, London, United Kingdom.

Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1. The IKZF1 group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1 definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1. The IKZF1 prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1 patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1 patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1 describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1 patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.
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http://dx.doi.org/10.1200/JCO.2017.74.3617DOI Listing
April 2018

Investigating the biology of relapsed acute leukemia: Proceedings of the Therapeutic Advances for Childhood Leukemia & Lymphoma (TACL) Consortium Biology Working Group.

Pediatr Hematol Oncol 2017 Sep - Oct;34(6-7):355-364. Epub 2017 Nov 30.

h Division of Pediatric Hematology and Oncology, Department of Pediatrics and OHSU Knight Cancer Institute , Oregon Health and Sciences University , Portland , OR , USA.

During the 2016 Therapeutic Advances for Childhood Leukemia & Lymphoma (TACL) Consortium investigators' meeting (Los Angeles, CA), a Biology Working Group was established to support the consortium's mission of developing innovative therapies for currently incurable childhood leukemias and lymphomas. The charge of the Biology Working Group was to address how TACL could advance biological investigations of pediatric relapsed/refractory hematologic malignancies while undertaking forward-looking therapeutic trials. To this end, the TACL Biology Committee was established to provide the scientific platform needed to further develop preclinical and translational studies that will advance the understanding and treatment of relapsed and refractory disease. The Biology Committee will focus on ensuring state-of-the-art studies that address biological components of early phase clinical trials, and developing a central biology bank of materials from these early phase trials for interrogations into the mechanisms of disease resistance.
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http://dx.doi.org/10.1080/08880018.2017.1395937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191173PMC
July 2018

Rac1 functions downstream of miR-142 in regulation of erythropoiesis.

Haematologica 2017 12 14;102(12):e476-e480. Epub 2017 Sep 14.

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot

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http://dx.doi.org/10.3324/haematol.2017.171736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709115PMC
December 2017