scholarly journals In vivo efficacy of B43 (anti-CD19)-pokeweed antiviral protein immunotoxin against human pre-B cell acute lymphoblastic leukemia in mice with severe combined immunodeficiency

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2201-2214 ◽  
Author(s):  
FM Uckun ◽  
C Manivel ◽  
D Arthur ◽  
LM Chelstrom ◽  
D Finnegan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Standard Errors ◽  
Combined Immunodeficiency ◽  
Pokeweed Antiviral Protein ◽  
Antiviral Protein ◽  
Kaplan Meier

Abstract A highly aggressive subclone of the human CALLA+C mu+ pre-B acute lymphoblastic leukemia (ALL) cell line NALM-6 (designated NALM-6-UM1) caused disseminated and fatal leukemia in CB.17 mice with severe combined immunodeficiency (SCID). An intravenous challenge with 1 x 10(6) (NALM-6-UM1 cells caused 15 of 27 (56%) SCID mice to become paraplegic at 31 +/- 2 days (median = 33 days) and 27 of 27 (100%) mice to die of disseminated leukemia at 38 +/- 1 days (median = 39 days). We used this SCID mouse model of aggressive human pre-B ALL to evaluate the in vivo antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin. A 3-day treatment with nontoxic doses of B43- PAP markedly reduced the incidence of paraplegia and improved event- free survival (EFS) in SCID mice challenged with 1 x 10(6) NALM-6-UM1 pre-B ALL cells, as reflected by significantly higher cumulative proportions of mice free of paraplegia or alive at 1 to 7 months, as compared with phosphate-buffered saline (PBS) treated control mice. The Kaplan-Meier estimates and standard errors of the probability of developing paraplegia after inoculation of 1 x 10(6) NALM-6-UM1 cells was 64% +/- 10% for PBS-treated mice (median time to paraplegia = 37 days) (N = 27), 18% +/- 8% for mice treated with 15 micrograms B43-PAP (5 micrograms/mouse/d x 3 days) (N = 23) and 5% +/- 5% for mice treated with 30 micrograms B43-PAP (10 micrograms/mouse/d x 3 days) (N = 21). While 27 of 27 PBS-treated control SCID mice died of leukemia at 38 +/- 1 days (range = 24 to 54 days), only 16 of 44 B43-PAP-treated mice developed leukemia at 74 +/- 12 days (range = 30 to 182 days), consistent with greater than or equal to 6 logs kill of clonogenic NALM- 6-UM1 cells in 64% of SCID mice. The Kaplan-Meier estimates and standard errors of the probability of long-term EFS after inoculation of 1 x 10(6) NALM-6-UM1 cells were 65% +/- 10% for mice treated with 15 micrograms B43-PAP and 60% +/- 11% for mice treated with 30 micrograms B43-PAP with a median survival time of greater than 7 months for both groups. In contrast, neither unconjugated B43 monoclonal antibody nor the anti-T-cell immunotoxin G17.2 (anti-CD4)-PAP decreased the incidence of paraplegia or improved EFS.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals In vivo efficacy of B43 (anti-CD19)-pokeweed antiviral protein immunotoxin against human pre-B cell acute lymphoblastic leukemia in mice with severe combined immunodeficiency

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2201-2214
Author(s):  
FM Uckun ◽  
C Manivel ◽  
D Arthur ◽  
LM Chelstrom ◽  
D Finnegan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Standard Errors ◽  
Combined Immunodeficiency ◽  
Pokeweed Antiviral Protein ◽  
Antiviral Protein ◽  
Kaplan Meier

A highly aggressive subclone of the human CALLA+C mu+ pre-B acute lymphoblastic leukemia (ALL) cell line NALM-6 (designated NALM-6-UM1) caused disseminated and fatal leukemia in CB.17 mice with severe combined immunodeficiency (SCID). An intravenous challenge with 1 x 10(6) (NALM-6-UM1 cells caused 15 of 27 (56%) SCID mice to become paraplegic at 31 +/- 2 days (median = 33 days) and 27 of 27 (100%) mice to die of disseminated leukemia at 38 +/- 1 days (median = 39 days). We used this SCID mouse model of aggressive human pre-B ALL to evaluate the in vivo antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin. A 3-day treatment with nontoxic doses of B43- PAP markedly reduced the incidence of paraplegia and improved event- free survival (EFS) in SCID mice challenged with 1 x 10(6) NALM-6-UM1 pre-B ALL cells, as reflected by significantly higher cumulative proportions of mice free of paraplegia or alive at 1 to 7 months, as compared with phosphate-buffered saline (PBS) treated control mice. The Kaplan-Meier estimates and standard errors of the probability of developing paraplegia after inoculation of 1 x 10(6) NALM-6-UM1 cells was 64% +/- 10% for PBS-treated mice (median time to paraplegia = 37 days) (N = 27), 18% +/- 8% for mice treated with 15 micrograms B43-PAP (5 micrograms/mouse/d x 3 days) (N = 23) and 5% +/- 5% for mice treated with 30 micrograms B43-PAP (10 micrograms/mouse/d x 3 days) (N = 21). While 27 of 27 PBS-treated control SCID mice died of leukemia at 38 +/- 1 days (range = 24 to 54 days), only 16 of 44 B43-PAP-treated mice developed leukemia at 74 +/- 12 days (range = 30 to 182 days), consistent with greater than or equal to 6 logs kill of clonogenic NALM- 6-UM1 cells in 64% of SCID mice. The Kaplan-Meier estimates and standard errors of the probability of long-term EFS after inoculation of 1 x 10(6) NALM-6-UM1 cells were 65% +/- 10% for mice treated with 15 micrograms B43-PAP and 60% +/- 11% for mice treated with 30 micrograms B43-PAP with a median survival time of greater than 7 months for both groups. In contrast, neither unconjugated B43 monoclonal antibody nor the anti-T-cell immunotoxin G17.2 (anti-CD4)-PAP decreased the incidence of paraplegia or improved EFS.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Effective immunochemotherapy of CALLA+C mu+ human pre-B acute lymphoblastic leukemia in mice with severe combined immunodeficiency using B43 (anti-CD19) pokeweed antiviral protein immunotoxin plus cyclophosphamide

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3116-3129 ◽  
Author(s):  
FM Uckun ◽  
LM Chelstrom ◽  
D Finnegan ◽  
L Tuel-Ahlgren ◽  
C Manivel ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Survival ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Leukemia Cells ◽  
Combined Immunodeficiency ◽  
Pokeweed Antiviral Protein ◽  
Antiviral Protein

Abstract A highly aggressive human CALLA+C mu+ pre-B acute lymphoblastic leukemia (ALL) cell line (NALM-6-UM1) causes disseminated and invariably fatal leukemia in CB.17 mice with severe combined immunodeficiency (SCID). We used this SCID mouse model of human pre-B ALL to evaluate and compare, in a total of 434 SCID mice, the antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin and cyclophosphamide (CPA) as individual reagents and as combined immunochemotherapeutic regimens. B43-PAP plus CPA was superior to either the immunotoxin or drug alone, and combined immunochemotherapy markedly improved the event-free survival (EFS) of SCID mice challenged with NALM-6-UM1 pre-B ALL cells. Notably, 90% to 100% of SCID mice challenged with 1 x 10(6) leukemia cells and then treated with B43-PAP plus CPA combined immunochemotherapy regimens became long-term survivors, a result not achieved with B43-PAP alone or CPA alone. The advantage was particularly evident in mice inoculated with 5 x 10(6) leukemia cells. While neither 15 micrograms B43-PAP (median survival, 58 days) nor 1 mg CPA (median survival, 49 days) resulted in long-term EFS of SCID mice challenged with 5 x 10(6) NALM-6- UM1 pre-B ALL cells, the probability of EFS at 6 months was 50% +/- 16% for SCID mice treated with 15 micrograms B43-PAP plus 1 mg CPA (median survival, greater than 180 days) (P less than .0001). The probability of long-term EFS was only 14% +/- 7% for mice treated with 30 micrograms B43-PAP and 0% +/- 0% for mice treated with 1 mg CPA, but 40% +/- 16% for mice treated with 30 micrograms B43-PAP plus 1 mg CPA (P less than .0001). Similarly, the probability of EFS at 6 months was 40% +/- 16% for mice treated with 2 mg CPA alone, 70% +/- 15% for mice treated with 2 mg CPA plus 15 micrograms B43-PAP, and 70% +/- 15% for mice treated with 2 mg CPA plus 30 micrograms B43-PAP. Ten SCID mice in the B43-PAP plus CPA combined immunochemotherapy arms surviving long term after the inoculation of 5 x 10(6) NALM-6-UM1 pre-B ALL cells were electively killed at 174 to 181 days to assess their leukemia burden. We found no evidence of leukemia in any of the bone marrow specimens by two-color immunofluorescence and multiparameter flow cytometry.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Effective immunochemotherapy of CALLA+C mu+ human pre-B acute lymphoblastic leukemia in mice with severe combined immunodeficiency using B43 (anti-CD19) pokeweed antiviral protein immunotoxin plus cyclophosphamide

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3116-3129 ◽  
Author(s):  
FM Uckun ◽  
LM Chelstrom ◽  
D Finnegan ◽  
L Tuel-Ahlgren ◽  
C Manivel ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Survival ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Leukemia Cells ◽  
Combined Immunodeficiency ◽  
Pokeweed Antiviral Protein ◽  
Antiviral Protein

A highly aggressive human CALLA+C mu+ pre-B acute lymphoblastic leukemia (ALL) cell line (NALM-6-UM1) causes disseminated and invariably fatal leukemia in CB.17 mice with severe combined immunodeficiency (SCID). We used this SCID mouse model of human pre-B ALL to evaluate and compare, in a total of 434 SCID mice, the antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin and cyclophosphamide (CPA) as individual reagents and as combined immunochemotherapeutic regimens. B43-PAP plus CPA was superior to either the immunotoxin or drug alone, and combined immunochemotherapy markedly improved the event-free survival (EFS) of SCID mice challenged with NALM-6-UM1 pre-B ALL cells. Notably, 90% to 100% of SCID mice challenged with 1 x 10(6) leukemia cells and then treated with B43-PAP plus CPA combined immunochemotherapy regimens became long-term survivors, a result not achieved with B43-PAP alone or CPA alone. The advantage was particularly evident in mice inoculated with 5 x 10(6) leukemia cells. While neither 15 micrograms B43-PAP (median survival, 58 days) nor 1 mg CPA (median survival, 49 days) resulted in long-term EFS of SCID mice challenged with 5 x 10(6) NALM-6- UM1 pre-B ALL cells, the probability of EFS at 6 months was 50% +/- 16% for SCID mice treated with 15 micrograms B43-PAP plus 1 mg CPA (median survival, greater than 180 days) (P less than .0001). The probability of long-term EFS was only 14% +/- 7% for mice treated with 30 micrograms B43-PAP and 0% +/- 0% for mice treated with 1 mg CPA, but 40% +/- 16% for mice treated with 30 micrograms B43-PAP plus 1 mg CPA (P less than .0001). Similarly, the probability of EFS at 6 months was 40% +/- 16% for mice treated with 2 mg CPA alone, 70% +/- 15% for mice treated with 2 mg CPA plus 15 micrograms B43-PAP, and 70% +/- 15% for mice treated with 2 mg CPA plus 30 micrograms B43-PAP. Ten SCID mice in the B43-PAP plus CPA combined immunochemotherapy arms surviving long term after the inoculation of 5 x 10(6) NALM-6-UM1 pre-B ALL cells were electively killed at 174 to 181 days to assess their leukemia burden. We found no evidence of leukemia in any of the bone marrow specimens by two-color immunofluorescence and multiparameter flow cytometry.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Biotherapy for xenografted human central nervous system leukemia in mice with severe combined immunodeficiency using B43 (anti-CD19)- pokeweed antiviral protein immunotoxin

Blood ◽  
1995 ◽  
Vol 85 (9) ◽  
pp. 2537-2545 ◽  
Author(s):  
R Gunther ◽  
LM Chelstrom ◽  
L Tuel-Ahlgren ◽  
J Simon ◽  
DE Myers ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Intrathecal Methotrexate ◽  
Appendicular Skeleton ◽  
Combined Immunodeficiency ◽  
Pokeweed Antiviral Protein ◽  
Antiviral Protein

The study of central nervous system (CNS) leukemia has been hampered by the lack of a suitable animal model. We report that severe combined immunodeficiency (SCID) mice invariably develop rapidly progressive fatal CNS leukemia within 3 weeks after intravenous injection of NALM-6 pre-B acute lymphoblastic leukemia (ALL) cells. Colonization of the dura mater and subarachnoid space, usually of the distal spinal cord with occasional extension into the Virchow-Robin spaces of blood vessels subjacent to the meninges, followed involvement of bone marrow in the skull, vertebrae, and, occasionally, the appendicular skeleton. Occult CNS leukemia was detectable by polymerase chain reaction amplification of human DNA as early as 8 days postinoculation of leukemia cells. We used this in vivo model of human CNS leukemia to examine the therapeutic efficacy and toxicity of intrathecally administered B43 (anti-CD19)-pokeweed antiviral protein (PAP), an anti-B-lineage ALL immunotoxin directed against the pan-B-cell antigen CD19/Bp95. Intrathecal therapy with B43 (anti-CD19)-PAP immunotoxin at nontoxic dose levels significantly improved survival of SCID mice and was superior to intrathecal methotrexate therapy.

scholarly journals Human t(4;11)(q21;q23) acute lymphoblastic leukemia in mice with severe combined immunodeficiency

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 859-865 ◽  
Author(s):  
FM Uckun ◽  
JR Downing ◽  
LM Chelstrom ◽  
R Gunther ◽  
M Ryan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Treatment Strategies ◽  
Disease Free Survival ◽  
Scid Mice ◽  
The Other ◽  
Combined Immunodeficiency ◽  
Disease Free ◽  
Overt Leukemia

Abstract Mice with severe combined immunodeficiency (SCID) were injected intravenously with primary bone marrow blasts from 12 children with newly diagnosed t(4;11)(q21;q23) acute lymphoblastic leukemia (ALL). Blasts from eight patients caused overt disseminated leukemia, whereas blasts from the other four patients produced occult leukemia that was detectable only by the polymerase chain reaction (PCR) technique. Only one patient among eight whose blasts caused disseminated leukemia in SCID mice remains alive and disease-free at 48.4 months postdiagnosis. In contrast, three of the other four patients whose blasts did not cause overt leukemia in SCID mice remain alive and disease-free at 6.1, 23.6, and 35.9 months, respectively. Thus, the occurrence of overt leukemia in SCID mice may be a predictor of patients' disease-free survival. The described SCID mouse model system may prove useful for designing more effective treatment strategies against therapy- refractory t(4;11) ALL.

An animal model for human cellular immunotherapy: specific eradication of human acute lymphoblastic leukemia by cytotoxic T lymphocytes in NOD/scid mice

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 654-660 ◽  
Author(s):  
Bart A. Nijmeijer ◽  
Roel Willemze ◽  
J. H. Frederik Falkenburg
Keyword(s):  
Animal Model ◽  
Acute Lymphoblastic Leukemia ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Human Acute Lymphoblastic Leukemia

Abstract Adoptive immunotherapy using in vitro–generated donor-derived cytotoxic T lymphocytes (CTLs) can be effective in the treatment of relapsed leukemia after allogeneic transplantation. To determine effector cell characteristics that result in optimal in vivo antileukemic efficacy, we developed an animal model for human CTL therapy. Nonobese diabetic/severe combined immunodeficiency (NOD/scid) mice were inoculated with either of 2 primary human acute lymphoblastic leukemia (ALL), denoted as SK and OF. Anti-SK and anti-OF CTLs were generated in vitro by repeated stimulation of donor peripheral blood mononuclear cells with either SK or OF cells. Both CTL lines displayed HLA-restricted reactivity against the original targets and non-major histocompatibility class (MHC)–restricted cross-reactivity in vitro. The CTLs were administered intravenously weekly for 3 consecutive weeks to mice engrafted with either SK or OF leukemia. In 3 of 8 SK-engrafted and anti-SK–treated mice, complete remissions were achieved in blood, spleen, and bone marrow. In the remaining 5 animals partial remissions were observed. In 4 of 4 OF-engrafted anti-OF–treated mice partial remissions were observed. The antileukemic effect of specific CTLs was exerted immediately after administration and correlated with the degree of HLA disparity of the donor-patient combination. In cross-combination–treated animals, no effect on leukemic progression was observed indicating that in vivo antileukemic reactivity is mediated by MHC-restricted effector cells. The CTLs, however, displayed an impaired in vivo proliferative capacity. Ex vivo analysis showed decreased reactivity as compared to the moment of infusion. We therefore conclude that the model can be used to explore the requirements for optimal in vivo efficacy of in vitro– generated CTLs.

scholarly journals Human t(4;11)(q21;q23) acute lymphoblastic leukemia in mice with severe combined immunodeficiency

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 859-865 ◽  
Author(s):  
FM Uckun ◽  
JR Downing ◽  
LM Chelstrom ◽  
R Gunther ◽  
M Ryan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Treatment Strategies ◽  
Disease Free Survival ◽  
Scid Mice ◽  
The Other ◽  
Combined Immunodeficiency ◽  
Disease Free ◽  
Overt Leukemia

Mice with severe combined immunodeficiency (SCID) were injected intravenously with primary bone marrow blasts from 12 children with newly diagnosed t(4;11)(q21;q23) acute lymphoblastic leukemia (ALL). Blasts from eight patients caused overt disseminated leukemia, whereas blasts from the other four patients produced occult leukemia that was detectable only by the polymerase chain reaction (PCR) technique. Only one patient among eight whose blasts caused disseminated leukemia in SCID mice remains alive and disease-free at 48.4 months postdiagnosis. In contrast, three of the other four patients whose blasts did not cause overt leukemia in SCID mice remain alive and disease-free at 6.1, 23.6, and 35.9 months, respectively. Thus, the occurrence of overt leukemia in SCID mice may be a predictor of patients' disease-free survival. The described SCID mouse model system may prove useful for designing more effective treatment strategies against therapy- refractory t(4;11) ALL.

scholarly journals Bone marrow from children in relapse with pre-B acute lymphoblastic leukemia proliferates and disseminates rapidly in scid mice

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2973-2981 ◽  
Author(s):  
S Kamel-Reid ◽  
M Letarte ◽  
M Doedens ◽  
A Greaves ◽  
B Murdoch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Growth Characteristics ◽  
Scid Mice ◽  
Leukemic Cells ◽  
Murine Bone Marrow ◽  
In Vivo Growth

Bone marrow samples from patients with pre-B acute lymphoblastic leukemia (pre-B ALL), either at diagnosis or at relapse, were transplanted into scid mice to determine whether these freshly obtained leukemic cells could proliferate in vivo and whether there were any differences in their in vivo growth characteristics. Cells from three patients who relapsed within 13 months of diagnosis proliferated rapidly in the murine bone marrow, spleen, and thymus, invaded peripheral organs, and resulted in morbidity and mortality of the animals within 4 to 16 weeks. Cells from two patients who relapsed 3.5 years after diagnosis grew much slower than the early relapse samples, taking up to 30 weeks to infiltrate the bone marrow of recipient mice. In contrast, leukemic cells were absent or were detected at low numbers in scid mice transplanted with cells obtained at diagnosis from three patients who have not yet relapsed. These results show an increased ability of leukemic cells from patients with aggressive lymphoblastic leukemia of poor prognosis to proliferate in scid mice.

scholarly journals Human t(1;19)(q23;p13) pre-B acute lymphoblastic leukemia in mice with severe combined immunodeficiency

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 3052-3062 ◽  
Author(s):  
FM Uckun ◽  
JR Downing ◽  
R Gunther ◽  
LM Chelstrom ◽  
D Finnegan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
Poor Prognosis ◽  
Scid Mouse ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Scid Mice ◽  
Newly Diagnosed ◽  
In Vivo Growth

Severe combined immunodeficient (SCID) mice were injected intravenously with 5 x 10(6) primary bone marrow (BM) blasts from newly diagnosed patients with E2A-PBX1 fusion transcript positive t(1;19)(q23;p13) pre- B acute lymphoblastic leukemia (ALL). A marked variation existed in the pattern and extent of leukemic cell engraftment in SCID mice challenged with t(1;19) pre-B ALL blasts. Blasts from some patients caused disseminated leukemia that was detected by histopathology and/or flow cytometry, whereas blasts from other patients produced occult leukemia that was only detected by flow cytometry and/or polymerase-chain reaction. Notably, the ability of primary t(1;19) pre-B ALL blasts to cause disseminated leukemia in SCID mice was associated with poor prognosis. Six of six patients whose blasts caused disseminated leukemia in SCID mice relapsed at a median of 7.8 months (range: 5.7 to 25.2 months). In contrast, the remaining four patients whose blasts did not engraft or only partially engrafted remain in complete remission at 28 to 47 months. A new E2A-PBX-1 fusion transcript positive t(1;19) pre- B ALL cell line (designated LC1;19) with the composite immunophenotype CD7-CD10+CD19+CD45-HLA-DR+C mu+ was established by expanding BM blasts from a SCID mouse, which died of human t(1;19) ALL at 7 weeks after inoculation of primary leukemic blasts from a t(1;19) ALL patient. This cell line caused disseminated and invariably fatal leukemia when greater than 10(4) cells were injected intravenously into SCID mice. Total body irradiation followed by syngeneic BM transplantation (BMT) showed limited efficacy against LC1;19 leukemia in SCID mice. To our knowledge, this study is the first to (1) examine the in vivo growth of primary t(1;19) pre-B ALL blasts in SCID mice and (2) show that leukemic blasts from a majority of newly diagnosed t(1;19) pre-B ALL patients cause disseminated human leukemia in SCID mice. Our results indicate that t(1;19) pre-B ALL is biologically heterogeneous with regard to its in vivo growth pattern in SCID mice, a feature that may be predictive of prognosis. The described LC1;19 SCID mouse model may prove particularly useful for designing more effective treatment strategies against poor-prognosis t(1;19) ALL.

Epithelial stem cell-mediated development of the human respiratory mucosa in SCID mice

2000 ◽  
Vol 113 (5) ◽  
pp. 767-778 ◽  
Author(s):  
A. Delplanque ◽  
C. Coraux ◽  
R. Tirouvanziam ◽  
I. Khazaal ◽  
E. Puchelle ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Sex Chromosome ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Functional Assay ◽  
Combined Immunodeficiency ◽  
Freezing And Thawing ◽  
Normal Epithelium ◽  
Tracheobronchial Epithelium

We have developed an in vivo assay for progenitor cells of the human tracheobronchial epithelium relying on the transplantation of human prenatal respiratory tissues into severe combined immunodeficiency mice. Engrafted embryonic or fetal open tracheobronchial rudiments are rapidly closed at each end by a neoformed membrane that we named the operculum. After 2–4 weeks, differentiated human respiratory epithelium covers both the native airway matrix and the new operculum. Human epithelial cells dissociated from either emerging embryonic lung primordia or mature xenografts were seeded in host human airway grafts, of which native epithelium had been eliminated by several cycles of freezing and thawing. All grafts seeded with donor epithelial cells and implanted back into SCID mice recovered a surface mucociliary epithelium expressing expected markers and secreting mucus. Spontaneous epithelium regrowth was never observed in control unseeded, denuded grafts. In some experiments, donor epithelial cells and host denuded airway were sex-mismatched and the donor origin of newly formed epithelial structures was confirmed by sex chromosome detection. After two rounds of seeding and reimplantation, a normal epithelium was observed to line the 3rd generation operculum. These observations substantiate a functional assay for human candidate airway epithelium stem cells.

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