B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells

Abstract The purpose of this study was to analyze the expression of B cell growth factor (BCGF) receptors and to elucidate the biologic effects of biochemically purified natural BCGF at the B cell precursor stage of human B lineage lymphoid differentiation. The specific binding of radioiodinated high-mol-wt BCGF (125I-HMW-BCGF) and low-molecular-wt BCGF (125I-LMW-BCGF) to fresh marrow blasts from B cell precursor acute lymphoblastic leukemia (ALL) patients was initially investigated. The estimated number of radioiodinated BCGF molecules bound per blast ranged from undetectable to 24.3 X 10(3) for HMW-BCGF, and from 11.5 X 10(3) to 457.8 X 10(3) for LMW-BCGF. In 3H-TdR incorporation assays, 75% of cases showed a significant response to LMW-BCGF with a median stimulation index of 9.3. By comparison, only 33% of cases showed a significant response to HMW-BCGF with a median stimulation index of 2.4. Subsequently, B cell precursor colony assays were performed to assess and compare the biologic effects of BCGF on leukemic B lineage lymphoid progenitor cells. Among 28 cases studied, 57% responded to both HMW-BCGF and LMW-BCGF, 21% responded only to LMW-BCGF, and the remaining cases showed no proliferative response to either growth factor. The response patterns of virtually pure populations of FACS- sorted leukemic B cell precursors were essentially identical to the proliferative responses of unsorted leukemic B-cell precursors. Synergistic effects between HMW-BCGF and LMW-BCGF were observed in 80% of the cases that responded to both. The numbers of cell-bound radioiodinated BCGF molecules, the stimulation indices, as well as the number of B cell precursor colonies in BCGF-stimulated cultures showed a marked interpatient variation. Patients with structural chromosomal abnormalities (SCAs) involving 12p11–13 or patients with a Philadelphia chromosome showed a greater HMW-BCGF response at the level of leukemic progenitor cells than did other patients (P = .02). The LMW-BCGF response was significantly greater for patients with SCA than for patients without SCA (P = .04). The response of leukemic progenitor cells to HMW-BCGF or LMW-BCGF did not correlate with sex, age, disease status, FAB morphology, WBC at diagnosis, or immunophenotype. To our knowledge, this study represents the first detailed analyses of BCGF receptor expression and BCGF effects in B cell precursor ALL. The data presented provide direct evidence for the expression of functional receptors for both HMW-BCGF and LMW-BCGF in B cell precursor ALL.

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B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells

Blood ◽

10.1182/blood.v70.4.1020.bloodjournal7041020 ◽

1987 ◽

Vol 70 (4) ◽

pp. 1020-1034 ◽

Cited By ~ 1

Author(s):

FM Uckun ◽

AS Fauci ◽

NA Heerema ◽

CW Song ◽

SR Mehta ◽

...

Keyword(s):

Growth Factor ◽

Cell Growth ◽

B Cell ◽

Progenitor Cells ◽

Stimulation Index ◽

Receptor Expression ◽

Cell Precursor ◽

B Cell Growth Factor ◽

B Lineage ◽

B Cell Precursors

The purpose of this study was to analyze the expression of B cell growth factor (BCGF) receptors and to elucidate the biologic effects of biochemically purified natural BCGF at the B cell precursor stage of human B lineage lymphoid differentiation. The specific binding of radioiodinated high-mol-wt BCGF (125I-HMW-BCGF) and low-molecular-wt BCGF (125I-LMW-BCGF) to fresh marrow blasts from B cell precursor acute lymphoblastic leukemia (ALL) patients was initially investigated. The estimated number of radioiodinated BCGF molecules bound per blast ranged from undetectable to 24.3 X 10(3) for HMW-BCGF, and from 11.5 X 10(3) to 457.8 X 10(3) for LMW-BCGF. In 3H-TdR incorporation assays, 75% of cases showed a significant response to LMW-BCGF with a median stimulation index of 9.3. By comparison, only 33% of cases showed a significant response to HMW-BCGF with a median stimulation index of 2.4. Subsequently, B cell precursor colony assays were performed to assess and compare the biologic effects of BCGF on leukemic B lineage lymphoid progenitor cells. Among 28 cases studied, 57% responded to both HMW-BCGF and LMW-BCGF, 21% responded only to LMW-BCGF, and the remaining cases showed no proliferative response to either growth factor. The response patterns of virtually pure populations of FACS- sorted leukemic B cell precursors were essentially identical to the proliferative responses of unsorted leukemic B-cell precursors. Synergistic effects between HMW-BCGF and LMW-BCGF were observed in 80% of the cases that responded to both. The numbers of cell-bound radioiodinated BCGF molecules, the stimulation indices, as well as the number of B cell precursor colonies in BCGF-stimulated cultures showed a marked interpatient variation. Patients with structural chromosomal abnormalities (SCAs) involving 12p11–13 or patients with a Philadelphia chromosome showed a greater HMW-BCGF response at the level of leukemic progenitor cells than did other patients (P = .02). The LMW-BCGF response was significantly greater for patients with SCA than for patients without SCA (P = .04). The response of leukemic progenitor cells to HMW-BCGF or LMW-BCGF did not correlate with sex, age, disease status, FAB morphology, WBC at diagnosis, or immunophenotype. To our knowledge, this study represents the first detailed analyses of BCGF receptor expression and BCGF effects in B cell precursor ALL. The data presented provide direct evidence for the expression of functional receptors for both HMW-BCGF and LMW-BCGF in B cell precursor ALL.

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Low molecular weight B cell growth factor induces proliferation of human B cell precursor acute lymphoblastic leukemias

Blood ◽

10.1182/blood.v70.1.132.bloodjournal701132 ◽

1987 ◽

Vol 70 (1) ◽

pp. 132-138 ◽

Cited By ~ 1

Author(s):

B Wormann ◽

SR Mehta ◽

AL Maizel ◽

TW LeBien

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Growth Factor ◽

Cell Growth ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Leukemic Cells ◽

Cell Precursor ◽

B Cell Growth Factor ◽

B Cell Precursors

Experiments were conducted to determine the effect of low mol wt B cell growth factor (L-BCGF) on B cell precursor acute lymphoblastic leukemia (ALL). L-BCGF induced a significant increase in 3H-TdR incorporation in 28 of 37 bone marrow aspirates from patients with B cell precursor ALL, with stimulation indices ranging from 2 to 129. Fluorescence-activated cell sorting confirmed that in five of seven patients the common acute lymphoblastic leukemia antigen (CALLA)/CD10 positive leukemic cells were responding directly to L-BCGF. L-BCGF was capable of inducing, in some patients, an increase in absolute viable cells and could also induce colony formation in vitro. The response of B cell precursor ALL was not attributable to beta IL 1, IL 2, or gamma interferon. These results indicate that the majority of B cell precursor ALL undergo a proliferative response to L-BCGF, suggesting a regulatory role for this lymphokine in the growth of B cell precursors.

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Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti- CD19 immunotoxins

Blood ◽

10.1182/blood.v71.1.13.13 ◽

1988 ◽

Vol 71 (1) ◽

pp. 13-29 ◽

Cited By ~ 134

Author(s):

FM Uckun ◽

W Jaszcz ◽

JL Ambrus ◽

AS Fauci ◽

K Gajl-Peczalska ◽

...

Keyword(s):

Molecular Weight ◽

Monoclonal Antibody ◽

Growth Factor ◽

Cell Growth ◽

B Cell ◽

Progenitor Cells ◽

Surface Marker ◽

Neoplastic Cells ◽

B Cell Growth Factor ◽

B Lineage

Abstract Extensive immunologic surface marker analyses and binding competition assays demonstrated that B43 monoclonal antibody (MoAb) is a new member of the CD19 cluster that recognizes the same surface epitope as several other anti-CD19 MoAbs. We used B43 MoAb to test for CD19 expression on neoplastic cells from 340 leukemia and 151 malignant lymphoma patients and on nonneoplastic cells in normal lymphohematopoietic and nonlymphohematopoietic tissues. Our study more than doubles the total number of cases with classified hematologic malignancies that have been examined for CD19 antigen expression. The data presented confirm that CD19 is the most reliable B lineage surface marker and support our view that this B lineage-restricted surface determinant may be an important functional receptor. Our findings provide unique and direct evidence that (a) CD19 is expressed on leukemic B lineage lymphoid progenitor cells freshly obtained from B lineage acute lymphoblastic leukemia patients but not on normal myeloid, erythroid, megakaryocytic, or multilineage bone marrow progenitor cells; (b) ligation of CD19 with B43 MoAb induces sustained increases in [Ca2+]i when crosslinked and inhibits high-molecular weight B cell growth factor (HMW-BCGF)-induced proliferation of activated B cells without affecting their low- molecular weight B cell growth factor (LMW-BCGF) response; therefore CD19 may be a unique signal receptor; (c) HMW-BCGF and LMW-BCGF augment expression of CD19, which suggests that CD19 and BCGF receptors may be under coordinate regulatory control; (d) approximately two million B43 MoAb molecules per cell can be bound to target B lineage lymphoma cells with a Ka of 1.9 x 10(8)/mol/L; (e) CD19 can undergo B43 MoAb-induced internalization; and (f) the opportunity is thus provided for using anti-CD19 MoAb to deliver toxins to B lineage neoplastic cells for more effective treatment of high-risk leukemia/lymphoma patients.

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Low molecular weight B cell growth factor induces proliferation of human B cell precursor acute lymphoblastic leukemias

Blood ◽

10.1182/blood.v70.1.132.132 ◽

1987 ◽

Vol 70 (1) ◽

pp. 132-138 ◽

Cited By ~ 26

Author(s):

B Wormann ◽

SR Mehta ◽

AL Maizel ◽

TW LeBien

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Growth Factor ◽

Cell Growth ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Leukemic Cells ◽

Cell Precursor ◽

B Cell Growth Factor ◽

B Cell Precursors

Abstract Experiments were conducted to determine the effect of low mol wt B cell growth factor (L-BCGF) on B cell precursor acute lymphoblastic leukemia (ALL). L-BCGF induced a significant increase in 3H-TdR incorporation in 28 of 37 bone marrow aspirates from patients with B cell precursor ALL, with stimulation indices ranging from 2 to 129. Fluorescence-activated cell sorting confirmed that in five of seven patients the common acute lymphoblastic leukemia antigen (CALLA)/CD10 positive leukemic cells were responding directly to L-BCGF. L-BCGF was capable of inducing, in some patients, an increase in absolute viable cells and could also induce colony formation in vitro. The response of B cell precursor ALL was not attributable to beta IL 1, IL 2, or gamma interferon. These results indicate that the majority of B cell precursor ALL undergo a proliferative response to L-BCGF, suggesting a regulatory role for this lymphokine in the growth of B cell precursors.

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Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti- CD19 immunotoxins

Blood ◽

10.1182/blood.v71.1.13.bloodjournal71113 ◽

1988 ◽

Vol 71 (1) ◽

pp. 13-29 ◽

Cited By ~ 1

Author(s):

FM Uckun ◽

W Jaszcz ◽

JL Ambrus ◽

AS Fauci ◽

K Gajl-Peczalska ◽

...

Keyword(s):

Molecular Weight ◽

Monoclonal Antibody ◽

Growth Factor ◽

Cell Growth ◽

B Cell ◽

Progenitor Cells ◽

Surface Marker ◽

Neoplastic Cells ◽

B Cell Growth Factor ◽

B Lineage

Extensive immunologic surface marker analyses and binding competition assays demonstrated that B43 monoclonal antibody (MoAb) is a new member of the CD19 cluster that recognizes the same surface epitope as several other anti-CD19 MoAbs. We used B43 MoAb to test for CD19 expression on neoplastic cells from 340 leukemia and 151 malignant lymphoma patients and on nonneoplastic cells in normal lymphohematopoietic and nonlymphohematopoietic tissues. Our study more than doubles the total number of cases with classified hematologic malignancies that have been examined for CD19 antigen expression. The data presented confirm that CD19 is the most reliable B lineage surface marker and support our view that this B lineage-restricted surface determinant may be an important functional receptor. Our findings provide unique and direct evidence that (a) CD19 is expressed on leukemic B lineage lymphoid progenitor cells freshly obtained from B lineage acute lymphoblastic leukemia patients but not on normal myeloid, erythroid, megakaryocytic, or multilineage bone marrow progenitor cells; (b) ligation of CD19 with B43 MoAb induces sustained increases in [Ca2+]i when crosslinked and inhibits high-molecular weight B cell growth factor (HMW-BCGF)-induced proliferation of activated B cells without affecting their low- molecular weight B cell growth factor (LMW-BCGF) response; therefore CD19 may be a unique signal receptor; (c) HMW-BCGF and LMW-BCGF augment expression of CD19, which suggests that CD19 and BCGF receptors may be under coordinate regulatory control; (d) approximately two million B43 MoAb molecules per cell can be bound to target B lineage lymphoma cells with a Ka of 1.9 x 10(8)/mol/L; (e) CD19 can undergo B43 MoAb-induced internalization; and (f) the opportunity is thus provided for using anti-CD19 MoAb to deliver toxins to B lineage neoplastic cells for more effective treatment of high-risk leukemia/lymphoma patients.

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B8.7 antigen is present on B-cell precursor acute lymphocytic leukemia. Correlation with the low molecular weight B-cell growth factor responsiveness of these cells

Blood ◽

10.1182/blood.v75.4.963.963 ◽

1990 ◽

Vol 75 (4) ◽

pp. 963-971 ◽

Cited By ~ 2

Author(s):

C Leprince ◽

N Blumenfeld ◽

G Flandrin ◽

P Galanaud ◽

F Sigaux ◽

...

Keyword(s):

Molecular Weight ◽

Growth Factor ◽

Cell Growth ◽

B Cell ◽

Lymphocytic Leukemia ◽

Low Molecular Weight ◽

Dependent Manner ◽

Cell Precursor ◽

B Cell Growth Factor ◽

Human B Cell

Abstract The purpose of this study was to analyze the expression of B8.7 antigen and its implication in the low molecular weight B-Cell growth factor (LMW BCGF) proliferative pathway at the early stages of the human B- cell differentiation. After an overnight incubation in culture medium of B-cell precursor acute lymphoblastic leukemias (ALL), we demonstrated the presence of B8.7 antigen in 18 of 25 cases (72%). Such an incubation also induced a significant increase in the LMW BCGF responsiveness of ALL cells (P less than 0.03). In addition, we showed a significant correlation between B8.7 expression and the ability of pre-B ALL cells to respond to LMW BCGF. As previously described for normal B cells, the anti-B8.7 monoclonal antibody inhibited the LMW BCGF-dependent proliferation of pre-B ALL cells in a dose-dependent manner. These data indicate that B8.7 antigen is expressed and may be functionally related to the LMW BCGF pathway at the pre-B cell stages of differentiation. These results also suggest that human B-cell precursor ALL are not only phenotypically similar to their normal B lymphocyte counterparts, but are also sensitive to the same immunoregulatory cytokines that control normal cell growth.

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B8.7 antigen is present on B-cell precursor acute lymphocytic leukemia. Correlation with the low molecular weight B-cell growth factor responsiveness of these cells

Blood ◽

10.1182/blood.v75.4.963.bloodjournal754963 ◽

1990 ◽

Vol 75 (4) ◽

pp. 963-971

Author(s):

C Leprince ◽

N Blumenfeld ◽

G Flandrin ◽

P Galanaud ◽

F Sigaux ◽

...

Keyword(s):

Molecular Weight ◽

Growth Factor ◽

Cell Growth ◽

B Cell ◽

Lymphocytic Leukemia ◽

Low Molecular Weight ◽

Dependent Manner ◽

Cell Precursor ◽

B Cell Growth Factor ◽

Human B Cell

The purpose of this study was to analyze the expression of B8.7 antigen and its implication in the low molecular weight B-Cell growth factor (LMW BCGF) proliferative pathway at the early stages of the human B- cell differentiation. After an overnight incubation in culture medium of B-cell precursor acute lymphoblastic leukemias (ALL), we demonstrated the presence of B8.7 antigen in 18 of 25 cases (72%). Such an incubation also induced a significant increase in the LMW BCGF responsiveness of ALL cells (P less than 0.03). In addition, we showed a significant correlation between B8.7 expression and the ability of pre-B ALL cells to respond to LMW BCGF. As previously described for normal B cells, the anti-B8.7 monoclonal antibody inhibited the LMW BCGF-dependent proliferation of pre-B ALL cells in a dose-dependent manner. These data indicate that B8.7 antigen is expressed and may be functionally related to the LMW BCGF pathway at the pre-B cell stages of differentiation. These results also suggest that human B-cell precursor ALL are not only phenotypically similar to their normal B lymphocyte counterparts, but are also sensitive to the same immunoregulatory cytokines that control normal cell growth.

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