CD10 and CD19 fluorescence intensity of B-cell precursors in normal and leukemic bone marrow. Clinical characterization of CD10+strong and CD10+weak common acute lymphoblastic leukemia

Heat shock protein 27 (hsp27) may function as a regulator of microfilament dynamics and may participate in signal transduction pathways of different cell growth regulators, with the mitogen- activated protein kinase-activated protein (MAPKAP) kinase 2 being a major enzyme responsible for its phosphorylation. Using two-dimensional gel electrophoresis, we have compared the expression levels of two hsp27 isoelectric variants (hsp27 isoforms) M2 (molecular weight, 26 kD; isoelectric point, 6.02) and M3 (molecular weight, 26 kD; isoelectric point, 5.60) in pediatric bone marrow CD19+CD10+B-cell precursors (BCPs) purified from either common acute lymphoblastic leukemia (c-ALL) patients, normal donors, or non-c-ALL patients. Compared with normal BCPs, we found increased hsp27 expressions (M2 isoform) (by a factor 5 to 9 of mean level) in c-ALL as well as in non- c-ALL (nonleukemic) precursors. Though increased phosphorylation of hsp27 (M3 isoform) was observed in BCPs from c-ALL patients at relapse (by a factor 3 of mean level compared with normal BCPs and precursors from c-ALL at diagnosis), which might represent a differential enzymatic activity, this was not distinguishable from that of non-c-ALL patients. Therefore, our studies suggest constitutive differences of hsp27 isoforms between pediatric leukemic BCPs and their relatively low- expressing, immunophenotypically normal bone marrow counterparts. In light of the occasional and possibly transient increase of hsp27 expression during nonleukemic BCP differentiation and the possible role of hsp27 in signal transduction to microfilaments, these differences might be of considerable biologic interest and of importance in future studies of regulated normal or dysregulated leukemic hematopoietic cellular differentiation.

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Expansion of polyclonal B-cell precursors in bone marrow from children treated for acute lymphoblastic leukemia

Hematology and Cell Therapy ◽

10.1007/s00282-997-0139-8 ◽

1997 ◽

Vol 39 (3) ◽

pp. 139-147 ◽

Cited By ~ 6

Author(s):

M. Duval ◽

O. Fenneteau ◽

H. Cave ◽

C. Gobillot ◽

P. Rohrlich ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Lymphoblastic Leukemia ◽

B Cell Precursors

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Analysis of the mechanism of adhesion of precursor-B acute lymphoblastic leukemia cells to bone marrow fibroblasts

Blood ◽

10.1182/blood.v82.11.3437.3437 ◽

1993 ◽

Vol 82 (11) ◽

pp. 3437-3444 ◽

Cited By ~ 38

Author(s):

K Bradstock ◽

V Makrynikola ◽

A Bianchi ◽

K Byth

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Leukemic Cell ◽

Inhibitory Effect ◽

Significant Inhibition ◽

Interleukin 4 ◽

Integrin Subunit ◽

B Cell Precursors

Abstract Normal B lymphopoiesis is dependent on a close relationship between B- cell precursors and the bone marrow (BM) microenvironment. To further understand the mechanisms regulating the proliferation of the malignant counterpart of B-cell precursors, namely precursor-B acute lymphoblastic leukemia (ALL), we examined the adhesion to BM fibroblasts (BMF) of 19 cases of precursor-B ALL using a chromium labeling assay. Eleven of 19 cases showed greater than 10% binding to BMF (range 2.3% to 54.8%, mean 19.1%). Binding was increased approximately twofold by preincubation of BMF with tumor necrosis factor and interleukin-4, which also resulted in upregulation of expression of vascular cell adhesion molecule-1 (VCAM-1) on BMF. The mechanism of attachment was investigated using murine monoclonal antibodies to leukocyte integrins, principally the beta, integrins VLA- 4 and VLA-5, which were demonstrated to be present on most cases by flow cytometry. Statistically significant inhibition of adhesion was observed with antibodies to the beta 1 common subunit, VLA-4, and VLA- 5, whereas little effect was seen with antibodies to VLA-6 or the beta 2 integrin subunit. Preincubation of fibroblasts with an antibody to VCAM-1 (a ligand of VLA-4) inhibited leukemic cell binding in the majority of cases, which was an effect also observed on cytokine- stimulated BMF. However, a minority of cases, as well as the pre-B lines NALM-6 and KM-3, showed no evidence of inhibition of adhesion with anti-VCAM-1 antibodies. Treatment of BMF with antifibronectin antibody alone had little effect on ALL adhesion and did not enhance the inhibitory effect of anti-VCAM-1. These data indicate that precursor-B ALL cells bind to BM stroma through the beta 1 integrins VLA-4 and VLA-5 and that this effect is partly mediated by VCAM-1 on stromal cells, although other undefined VLA ligands are also likely to be involved. Attachment of ALL cells to stroma is likely to play a key role in regulating the survival and growth of these cells through exposure to stromal cytokines.

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Analysis of the mechanism of adhesion of precursor-B acute lymphoblastic leukemia cells to bone marrow fibroblasts

Blood ◽

10.1182/blood.v82.11.3437.bloodjournal82113437 ◽

1993 ◽

Vol 82 (11) ◽

pp. 3437-3444 ◽

Cited By ~ 1

Author(s):

K Bradstock ◽

V Makrynikola ◽

A Bianchi ◽

K Byth

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Leukemic Cell ◽

Inhibitory Effect ◽

Significant Inhibition ◽

Interleukin 4 ◽

Integrin Subunit ◽

B Cell Precursors

Normal B lymphopoiesis is dependent on a close relationship between B- cell precursors and the bone marrow (BM) microenvironment. To further understand the mechanisms regulating the proliferation of the malignant counterpart of B-cell precursors, namely precursor-B acute lymphoblastic leukemia (ALL), we examined the adhesion to BM fibroblasts (BMF) of 19 cases of precursor-B ALL using a chromium labeling assay. Eleven of 19 cases showed greater than 10% binding to BMF (range 2.3% to 54.8%, mean 19.1%). Binding was increased approximately twofold by preincubation of BMF with tumor necrosis factor and interleukin-4, which also resulted in upregulation of expression of vascular cell adhesion molecule-1 (VCAM-1) on BMF. The mechanism of attachment was investigated using murine monoclonal antibodies to leukocyte integrins, principally the beta, integrins VLA- 4 and VLA-5, which were demonstrated to be present on most cases by flow cytometry. Statistically significant inhibition of adhesion was observed with antibodies to the beta 1 common subunit, VLA-4, and VLA- 5, whereas little effect was seen with antibodies to VLA-6 or the beta 2 integrin subunit. Preincubation of fibroblasts with an antibody to VCAM-1 (a ligand of VLA-4) inhibited leukemic cell binding in the majority of cases, which was an effect also observed on cytokine- stimulated BMF. However, a minority of cases, as well as the pre-B lines NALM-6 and KM-3, showed no evidence of inhibition of adhesion with anti-VCAM-1 antibodies. Treatment of BMF with antifibronectin antibody alone had little effect on ALL adhesion and did not enhance the inhibitory effect of anti-VCAM-1. These data indicate that precursor-B ALL cells bind to BM stroma through the beta 1 integrins VLA-4 and VLA-5 and that this effect is partly mediated by VCAM-1 on stromal cells, although other undefined VLA ligands are also likely to be involved. Attachment of ALL cells to stroma is likely to play a key role in regulating the survival and growth of these cells through exposure to stromal cytokines.

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Differential expression levels of the heat shock protein 27 isoforms in pediatric normal, nonleukemic and common acute lymphoblastic leukemia B- cell precursors

Blood ◽

10.1182/blood.v85.2.510.510 ◽

1995 ◽

Vol 85 (2) ◽

pp. 510-521 ◽

Cited By ~ 8

Author(s):

PS Madsen ◽

P Hokland ◽

N Clausen ◽

J Ellegaard ◽

M Hokland

Keyword(s):

Signal Transduction ◽

Molecular Weight ◽

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Heat Shock ◽

Heat Shock Protein ◽

B Cell ◽

Isoelectric Point ◽

Lymphoblastic Leukemia ◽

B Cell Precursors

Abstract Heat shock protein 27 (hsp27) may function as a regulator of microfilament dynamics and may participate in signal transduction pathways of different cell growth regulators, with the mitogen- activated protein kinase-activated protein (MAPKAP) kinase 2 being a major enzyme responsible for its phosphorylation. Using two-dimensional gel electrophoresis, we have compared the expression levels of two hsp27 isoelectric variants (hsp27 isoforms) M2 (molecular weight, 26 kD; isoelectric point, 6.02) and M3 (molecular weight, 26 kD; isoelectric point, 5.60) in pediatric bone marrow CD19+CD10+B-cell precursors (BCPs) purified from either common acute lymphoblastic leukemia (c-ALL) patients, normal donors, or non-c-ALL patients. Compared with normal BCPs, we found increased hsp27 expressions (M2 isoform) (by a factor 5 to 9 of mean level) in c-ALL as well as in non- c-ALL (nonleukemic) precursors. Though increased phosphorylation of hsp27 (M3 isoform) was observed in BCPs from c-ALL patients at relapse (by a factor 3 of mean level compared with normal BCPs and precursors from c-ALL at diagnosis), which might represent a differential enzymatic activity, this was not distinguishable from that of non-c-ALL patients. Therefore, our studies suggest constitutive differences of hsp27 isoforms between pediatric leukemic BCPs and their relatively low- expressing, immunophenotypically normal bone marrow counterparts. In light of the occasional and possibly transient increase of hsp27 expression during nonleukemic BCP differentiation and the possible role of hsp27 in signal transduction to microfilaments, these differences might be of considerable biologic interest and of importance in future studies of regulated normal or dysregulated leukemic hematopoietic cellular differentiation.

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Faculty Opinions recommendation of Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726364889.793551058 ◽

2018 ◽

Author(s):

Jan Starý

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Cell Precursor

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Co-culture model of B-cell acute lymphoblastic leukemia recapitulates a transcription signature of chemotherapy-refractory minimal residual disease

Scientific Reports ◽

10.1038/s41598-021-95039-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Stephanie L. Rellick ◽

Gangqing Hu ◽

Debra Piktel ◽

Karen H. Martin ◽

Werner J. Geldenhuys ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Tumor Cells ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Adherent Cells ◽

Cell Acute Lymphoblastic Leukemia ◽

Minimal Residual

AbstractB-cell acute lymphoblastic leukemia (ALL) is characterized by accumulation of immature hematopoietic cells in the bone marrow, a well-established sanctuary site for leukemic cell survival during treatment. While standard of care treatment results in remission in most patients, a small population of patients will relapse, due to the presence of minimal residual disease (MRD) consisting of dormant, chemotherapy-resistant tumor cells. To interrogate this clinically relevant population of treatment refractory cells, we developed an in vitro cell model in which human ALL cells are grown in co-culture with human derived bone marrow stromal cells or osteoblasts. Within this co-culture, tumor cells are found in suspension, lightly attached to the top of the adherent cells, or buried under the adherent cells in a population that is phase dim (PD) by light microscopy. PD cells are dormant and chemotherapy-resistant, consistent with the population of cells that underlies MRD. In the current study, we characterized the transcriptional signature of PD cells by RNA-Seq, and these data were compared to a published expression data set derived from human MRD B-cell ALL patients. Our comparative analyses revealed that the PD cell population is markedly similar to the MRD expression patterns from the primary cells isolated from patients. We further identified genes and key signaling pathways that are common between the PD tumor cells from co-culture and patient derived MRD cells as potential therapeutic targets for future studies.

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Death induction by CD99 ligation in TEL/AML1-positive acute lymphoblastic leukemia and normal B cell precursors

Journal of Leukocyte Biology ◽

10.1189/jlb.0210097 ◽

2010 ◽

Vol 88 (2) ◽

pp. 405-412 ◽

Cited By ~ 21

Author(s):

Z. Husak ◽

D. Printz ◽

A. Schumich ◽

U. Potschger ◽

M. N. Dworzak

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Lymphoblastic Leukemia ◽

B Cell Precursors

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High cortactin expression in B-cell acute lymphoblastic leukemia is associated with increased transendothelial migration and bone marrow relapse

Leukemia ◽

10.1038/s41375-018-0333-4 ◽

2018 ◽

Vol 33 (6) ◽

pp. 1337-1348 ◽

Cited By ~ 3

Author(s):

Martha Velázquez-Avila ◽

Juan Carlos Balandrán ◽

Dalia Ramírez-Ramírez ◽

Mirella Velázquez-Avila ◽

Antonio Sandoval ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Transendothelial Migration ◽

Cell Acute Lymphoblastic Leukemia

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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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