TEL-AML1 Transgenic Zebrafish Model of Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 102-102 ◽  
Author(s):  
Hatem E. Sabaawy ◽  
Mizuki Azuma ◽  
Lisa Embree ◽  
Matthew F. Starost ◽  
Dennis D. Hickstein
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Large Scale ◽  
Lymphoblastic Leukemia ◽  
Fluorescent Microscopy ◽  
Targeted Mutagenesis ◽  
Transgenic Zebrafish ◽  
Lymphoid Progenitors ◽  
Transgenic Lines

Abstract TEL-AML1 (ETV6-RUNX1) fusion is the product of the t(12;21) chromosomal translocation, the most common chromosomal rearrangement in childhood cancer. The translocation fuses two highly conserved transcription factors, TEL and AML1 that have essential roles in hematopoiesis. Genetic studies of identical twins with concordant leukemia, the detection of leukemia-specific fusion genes in neonatal blood spots, and the existence of multiple leukemic subclones at ALL diagnosis point to prenatal origin of the fusion and long latency before leukemia development. Additionally, a study in growth factor-dependent cell lines and transgenic mice, and several mouse transplant models suggest that TEL-AML1 is insufficient by itself for leukemic transformation. To determine whether TEL-AML1 has selective transforming impact on a particular stem cell lineage, we established stable zebrafish transgenic lines expressing the TEL-AML1 fusion protein both constitutively, and within the lymphoid progenitors. In these lines, either the zebrafish β-actin (ZBA) promoter or the xenopus elongation factor-1 (XEF1) promoter drives TEL-AML1 expression constitutively, while the zebrafish RAG-2 promoter (RAG2) selectively drives TEL-AML1 expression in committed lymphocyte precursors, but not in earlier multilineage hematopoietic precursors. TEL-AML1 expression, alone or fused to EGFP, was detected at 24-hour post fertilization (hpf) with fluorescent microscopy or RT-PCR and confirmed with western blot analysis. In-Situ Hybridization and confocal microscopy revealed that transgenic zebrafish maintained TEL-AML1 expression throughout adulthood. The expression of TEL-AML1 was associated with accumulation of immature hematopoietic progenitor cells, mostly in the kidney and spleen of several transgenic zebrafish lines, within a few weeks of development, indicating an expansion of the progenitor cell population. To date, a small number (5 out of 391 transgenic fish; 1.3%) of founders and progeny of zebrafish transgenic for ZBA- or XEF1-TEL-AML1 fusion developed an infiltrating lymphoid neoplasm, most likely acute lymphoblastic leukemia with a latency of 8–12 month. The lymphoblasts were negative for myeloperoxidase and PAS staining, with abundant expression of both EGFP in lymphoblasts from EGFP-TEL-AML1 line, and pre-B-cell leukemia transcription factor-1 (PBX1; also called cALLa) indicating that Leukemias originated in a TEL-AML1 expressing cell(s), and mimic the human CD10-positive precursor-B cell ALL. None of 350 wild-type, 125 control EGFP fish or 353 RAG2-TEL-AML1 transgenic zebrafish had any leukemia or hematopoietic changes. Therefore, the expression of TEL-AML1 fusion in our ZBA- and XEF1-TEL-AML1 transgenic lines generates a premalignant state, which appears to require additional genetic events for acquisition of the leukemic phenotype. The fact that none of the RAG2 zebrafish expressing TEL-AML1 in committed lymphoid progenitors developed leukemia or progenitor expansion indicates that the leukemic stem cell associated with TEL-AML1 leukemia is an immature progenitor earlier than the committed lymphoid progenitors where RAG2 expression is detected. The TEL-AML1 transgenic zebrafish lines provide a basis for large scale and targeted mutagenesis screens aimed at identifying mutations and cooperating events that are required for TEL-AML1 induced leukemias.

scholarly journals TEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia

2006 ◽  
Vol 103 (41) ◽  
pp. 15166-15171 ◽  
Author(s):  
H. E. Sabaawy ◽  
M. Azuma ◽  
L. J. Embree ◽  
H.-J. Tsai ◽  
M. F. Starost ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Inotuzumab Ozogamicin (Ino) May Overcome the Impact of Philadelphia Chromosome (Ph)-like Phenotype in Adult Patients (pts) with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1641-1641 ◽  
Author(s):  
Elias Jabbour ◽  
Kathryn G. Roberts ◽  
Koji Sasaki ◽  
Yaqi Zhao ◽  
Chunxu Qu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
The Impact

Background: Ino showed significant activity in phase II trials in pts with R/R ALL, that was subsequently confirmed in Phase III trial where Ino demonstrated higher response rates and superior overall survival vs standard of care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).Ph-like or BCR-ABL1-like ALL possesses a gene expression profile similar to that of BCR-ABL1 ALL but lacks the BCR-ABL1 fusion protein. It is characterized by increased expression of hematopoietic stem-cell genes, deletion of B-cell lineage genes and kinase-activating alterations. Ph-like ALL is associated with refractoriness to standard induction/consolidation chemotherapy and poor prognosis. Aim: To evaluate the outcomes of pts with R/R Ph-like ALL treated in phase II trial with Ino monotherapy. Methods: We performed an integrated analysis of whole genome sequencing (to identify sequence mutations, structural variations and DNA copy number alterations), and transcriptome sequencing (RNAseq; to quantify gene expression, determine Ph-like gene expression profile and identify fusions) on 53 patients' samples treated with Ino between June 2010 and September 2012. Results: Fifty-three evaluable pts with R/R ALL with stored baseline samples were analyzed. Pts characteristics are summarized in Table 1. Median age was 50 years. Ino was given as Salvage 1, Salvage 2, and Salvage 3 and beyond in 20 (38%), 18 (34%), and 15 (28%) pts, respectively. Figure 1 reflects the different genomic subgroups identified among 53 evaluable pts. Ph-like gene signature was found in 12 pts (22.6%). Among these 12 pts, 6 had IGH-CRLF2, 2 IGH-EPOR, 1 SNX2-ABL1, and 3 had no fusions identified. The overall response rates (ORR) were 54% [complete remission (CR) 20%, CR with partial hematologic recovery (CRh) 32%, and marrow CR (CRi) 2%]. Among pts with morphologic remission, 46% and 82% achieved minimal residual disease (MRD) negativity at CR and at any time, respectively. The ORR for pts with Ph-like ALL, Ph-positive ALL, ALL with KMT2A, and others were 58% (CR=25%; CRh=33%), 42% (CR=8%; CRh=33%), 57% (CR=14%; CRh=29%; CRi=14%), and 56% (CR=26%; CRh=30%), respectively. The respective overall MRD negativity rates were 71%, 100%, 75%, and 83% (Table 1). The median follow-up was 60 months. The median event-free (EFS) and overall survival (OS) were 3.3 and 5.4 months, respectively. There was no difference in EFS and OS between the subgroups analyzed (P=0.464; P=0.824). The median EFS and OS were 4.5 and 4.5 months for pts with Ph-like, 3.1 and 7.2 months for those with Ph-positive ALL, 2.8 and 4.4 months for those with KMT2A, and 2.2 and 4.6 months for others (Table 1). 21 (40%) pts had subsequent allogeneic stem cell transplant; 6 (50%), 3 (25%), 4 (57%), and 8 (36%) in each subgroup, respectively. The rate of VOD was 3 (6%) with no difference among different subgroups. Conclusion: The current analysis suggest that Ino therapy may overcome the impact of Ph-like phenotype in pts with ALL. Confirmation of these findings in a larger cohort and in frontline ALL patients is needed. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Cellectis: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding. Mullighan:Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria.

A Successful Re-Induction Regimen for Relapsed Pediatric Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 863-863
Author(s):  
Jason Ackerman ◽  
Douglas Hawkins ◽  
Karyn Brundige ◽  
Laura Eisenberg ◽  
Blythe Thomson
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Induction Regimen ◽  
First Relapse

Abstract Background: Acute Lymphoblastic Leukemia (ALL) is the most common form of malignancy in children. Advances in treatments have made ALL the disease highly curable; however relapse is the most common form of treatment failure. The prognosis for relapsed ALL is poor, and the ability to achieve a durable second remission is influenced by the length of the initial remission and, potentially, the re-induction therapy chosen. We present a series of 60 pediatric ALL patients with first relapse (54 pre B-cell and 6 T-cell) treated with a standardized four-drug induction therapy followed by either intensification therapy or hematopoietic stem cell transplant (HSCT). Methods: Patients treated at Children’s Hospital and Regional Medical Center, Seattle, WA with a common re-induction regimen for first relapse ALL were reviewed in this IRB-approved retrospective study. Patients included isolated or combined bone marrow (BM) relapse, isolated central nervous system (CNS) relapse alone, or isolated testicular relapse. Re-induction consisted of a four-drug combination of dexamethasone (dex) (day 0-6, 14-20), vincristine (VCR) (weekly for 4 weeks), peg-aspargase (weekly for 4 weeks), and idarubicin (10 mg/m2/day × 2-3 doses) and intrathecal triple (ITT) drug therapy. After achieving second complete remission (CR2), patients proceeded to HSCT or continued chemotherapy at the discretion of the physician. Allogeneic HSCT was total body irradiation based and a variety of stem cell sources. Continuation chemotherapy was alternating blocks every 3 weeks for up to 8 courses: Block A, consisting of dex, VCR, 6-thioguanine (TG), peg-asparagase and methotrexate (MTX) and ITT, and Block B, consisting of etoposide and ifosfamide and ITT. Maintenance chemotherapy with MTX, VCR and TG with cranial, craniospinal or testicular radiation completed the two year regimen. Results: Among the 54 pre-B-cell patients, there were 32 with BM relapse (either isolated or with CNS), 16 CNS relapses, and 6 testicular relapses. CR2 was achieved in 96% of the patients. Two did not achieve remission, dying of toxicity during re-induction. BM (± CNS) Isolated CNS Testicular Duration of CR1 n 3 yr. EFS (95% CI) n 3 yr. EFS (95% CI) n 3 yr. EFS (95% CI) <18 months 5 0% (± 52%) 3 67% (± 54%) - - >18 months 27 39% (± 24%) 13 75% (± 26%) 6 67% (± 38%) Among the patients with BM relapse, the 3 year Event Free Survival (EFS) was 33.2% (95% CI: ± 20.8%). The 3 year EFS for the 18 who proceeded to HSCT was 35.0% (95% CI: ± 27.4%), while 3-year EFS for chemotherapy only patients was 31.7% (95% CI: ± 31.8%). There were 6 patients with T-cell relapsed disease, which were evaluated separately. Their EFS was 0% (95% CI: ±46%) at three years, and 2 failed to achieve CR2. Discussion: We present a large single institution series of patients treated with a common reinduction regimen followed by chemotherapy or HSCT. Although intensive, the regimen was tolerable (less than 4% toxic death rate) and highly successful in achieving CR2. Among the patients with later BM relapse, there was minimal difference in 3-year EFS between chemotherapy and HSCT, offering a reasonable continuation chemotherapy regimen to these patients. Our data confirmed the excellent outcome of isolated CNS and testicular relapse and the poor outcome of very early relapse and T cell disease.

scholarly journals E2a/Pbx1 Induces the Rapid Proliferation of Stem Cell Factor-Dependent Murine Pro-T Cells That Cause Acute T-Lymphoid or Myeloid Leukemias in Mice

2004 ◽  
Vol 24 (3) ◽  
pp. 1256-1269 ◽  
Author(s):  
David B. Sykes ◽  
Mark P. Kamps
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Cell Division ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Stem Cell Factor ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Acute Myeloid

ABSTRACT Oncoprotein E2a/Pbx1 is produced by the t(1;19) chromosomal translocation of human pre-B acute lymphoblastic leukemia. E2a/Pbx1 blocks differentiation of primary myeloid progenitors but, paradoxically, induces apoptosis in established pre-B-cell lines, and no transforming function of E2a/Pbx1 has been reported in cultured lymphoid progenitors. Here, we demonstrate that E2a/Pbx1 induces immortal proliferation of stem cell factor (SCF)-dependent pro-T thymocytes by a mechanism dependent upon both its transactivation and DNA-binding functions. E2a-Pbx1 cooperated with cytokines or activated signaling oncoproteins to induce cell division, as inactivation of conditional E2a/Pbx1 in either factor-dependent pro-T cells or pro-T cells made factor independent by expression of Bcr/Abl resulted in pro-T-cell quiescence, while reactivation of E2a/Pbx1 restored cell division. Infusion of E2a/Pbx1 pro-T cells in mice caused T lymphoblastic leukemia and, unexpectedly, acute myeloid leukemia. The acute lymphoblastic leukemia did not evidence further maturation, suggesting that E2a/Pbx1 establishes an early block in pro-T-cell development that cannot be overcome by marrow or thymic microenvironments. In an E2a/Pbx1 pro-T thymocyte clone that induced only pro-T acute lymphoblastic leukemia, coexpression of Bcr/Abl expanded its leukemic phenotype to include acute myeloid leukemia, suggesting that unique functions of cooperating signaling oncoproteins can influence the lymphoid versus myeloid character of E2a/Pbx1 leukemia and may cooperate with E2a/Pbx1 to dictate the pre-B-cell phenotype of human leukemia containing t(1;19).

Sign in / Sign up

Export Citation Format

Share Document