Leukemogenic Cascade Induced by a Constitutively Active Neurotrophin Receptor, ΔTrkA.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1442-1442
Author(s):  
Zhixiong Li ◽  
Johann Meyer ◽  
Mathias Rhein ◽  
Olga Kustikova ◽  
Cornelia Rudolph ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinases ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Insertion Site ◽  
Leukemic Cells ◽  
Neurotrophin Receptor ◽  
Target Cells ◽  
Receptor Signaling ◽  
Lymphoid Leukemia

Abstract Various neurotrophins (NT) are expressed in the hematopoietic microenvironment to deliver their signals through TRK receptor tyrosine kinases. Although previous reports suggested a transforming potential of activated TRK signaling in hematopoiesis, the target cells and underlying mechanisms are largely unknown. In this study, we investigated in vivo leukemogenesis of ΔTrkA, a mutant of TRKA isolated from a patient with acute myeloid leukemia (AML). Retroviral expression of ΔTrkA in myeloid 32D cells induced AML at ~4 weeks after transplantation into syngeneic C3H/Hej mice (n=11). C57BL/6J mice (n=15) transplanted with ΔTrkA-transduced primary bone marrow cells developed myeloid and/or lymphoid leukemia with infiltration in multiple organs including bone marrow, spleen, liver, lung, and central nervous system. While activation of a tyrosine kinase generally is not sufficient to cause AML, surprisingly, 7 out of 15 C57BL/6J mice developed a polyclonal AML with a latency of <12 days. This strongly suggests that ΔTrkA is sufficient to block differentiation and promote proliferation of short-term repopulating myeloid progenitor cells. This simultaneous interference with two complementary leukemogenic pathways has not been reported for other oncogenic tyrosine kinases. However, as half of the mice survived this disorder, ΔTrkA does not seem to confer self-renewal properties to transformed blasts. Supporting this hypothesis, transplantation into lethally irradiated secondary recipients did not re-induce polyclonal AML, but rather gave rise to clonal acute lymphoblastic leukemia (ALL) after a latency of >78 days. This suggests that ΔTrkA can also transform long-term repopulating cells with a lymphoid potential. Retroviral insertion site analyses and spectral karyotyping revealed that induction of ALL by ΔTrkA required additional genetic lesions: Leukemic cells showed retroviral insertions in proto-oncogenes Bcl11a and Bcl11b, among others. Characterization of signal transduction demonstrated that PI3K and mTOR-raptor were crucial components of the transforming pathway induced by ΔTrkA. Phospholipase D was an important contributing factor, whereas STAT and MAP kinase pathways were not involved. In summary, our findings reveal potent transforming properties of altered NT receptor signaling in leukemia induction, which are in many respects distinct from other oncogenic tyrosine kinases. We would suggest to further evaluate the role of NT receptor signaling in leukemia pathogenesis, prognosis and treatment.

scholarly journals Colony formation in vitro by leukemic cells in acute lymphoblastic leukemia (ALL)

Blood ◽  
1978 ◽  
Vol 52 (4) ◽  
pp. 712-718 ◽  
Author(s):  
SD Smith ◽  
EM Uyeki ◽  
JT Lowman
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Lymphoid Cells ◽  
Assay System ◽  
Leukemic Cells ◽  
Specific Cell ◽  
Specific Cell Surface

Abstract An assay system in vitro for the growth of malignant lymphoblastic colony-forming cells (CFC) was established. Growth of malignant myeloblastic CFC has been previously reported, but this is the first report of growth of malignant lymphoblastic CFC. Established assay systems in vitro have been very helpful in elucidating the control of growth and differentiation of both normal and malignant bone marrow cells. Lymphoblastic CFC were grown from the bone marrow aspirates of 20 children with acute lymphoblastic leukemia. Growth of these colonies was established on an agar assay system and maintained in the relative hypoxia (7% oxygen) of a Stulberg chamber. The criteria for malignancy of these colonies was based upon cellular cytochemical staining characteristics, the presence of specific cell surface markers, and the ability of these lymphoid cells to grow without the addition of a lymphoid mitogen. With this technique, specific nutritional requirements and drug sensitivities can be established in vitro, and these data may permit tailoring of individual antileukemic therapy.

scholarly journals Inhibition of Apoptosome Formation by Suppression of Hsp90β Phosphorylation in Tyrosine Kinase-Induced Leukemias

2008 ◽  
Vol 28 (17) ◽  
pp. 5494-5506 ◽  
Author(s):  
Manabu Kurokawa ◽  
Chen Zhao ◽  
Tannishtha Reya ◽  
Sally Kornbluth
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Tyrosine Kinases ◽  
Bone Marrow Cells ◽  
Leukemic Cells ◽  
Mouse Bone Marrow ◽  
Mitochondrial Cytochrome ◽  
Caspase 9 ◽  
Normal Cells ◽  
Mouse Bone Marrow Cells

ABSTRACT Constitutively active tyrosine kinases promote leukemogenesis by increasing cell proliferation and inhibiting apoptosis. However, mechanisms underlying apoptotic inhibition have not been fully elucidated. In many settings, apoptosis occurs by mitochondrial cytochrome c release, which nucleates the Apaf-1/caspase-9 apoptosome. Here we report that the leukemogenic kinases, Bcr-Abl, FLT3/D835Y, and Tel-PDGFRβ, all can inhibit apoptosome function. In cells expressing these kinases, the previously reported apoptosome inhibitor, Hsp90β, bound strongly to Apaf-1, preventing cytochrome c-induced Apaf-1 oligomerization and caspase-9 recruitment. Hsp90β interacted weakly with the apoptosome in untransformed cells. While Hsp90β was phosphorylated at Ser 226/Ser 255 in untransformed cells, phosphorylation was absent in leukemic cells. Expression of mutant Hsp90β (S226A/S255A), which mimics the hypophosphorylated form in leukemic cells, conferred resistance to cytochrome c-induced apoptosome activation in normal cells, reflecting enhanced binding of nonphosphorylatable Hsp90β to Apaf-1. In Bcr-Abl-positive mouse bone marrow cells, nonphosphorylatable Hsp90β expression conferred imatinib (Gleevec) resistance. These data provide an explanation for apoptosome inhibition by activated leukemogenic tyrosine kinases and suggest that alterations in Hsp90β-apoptosome interactions may contribute to chemoresistance in leukemias.

scholarly journals Colony formation in vitro by leukemic cells in acute lymphoblastic leukemia (ALL)

Blood ◽  
1978 ◽  
Vol 52 (4) ◽  
pp. 712-718 ◽  
Author(s):  
SD Smith ◽  
EM Uyeki ◽  
JT Lowman
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Lymphoid Cells ◽  
Assay System ◽  
Leukemic Cells ◽  
Specific Cell ◽  
Specific Cell Surface

An assay system in vitro for the growth of malignant lymphoblastic colony-forming cells (CFC) was established. Growth of malignant myeloblastic CFC has been previously reported, but this is the first report of growth of malignant lymphoblastic CFC. Established assay systems in vitro have been very helpful in elucidating the control of growth and differentiation of both normal and malignant bone marrow cells. Lymphoblastic CFC were grown from the bone marrow aspirates of 20 children with acute lymphoblastic leukemia. Growth of these colonies was established on an agar assay system and maintained in the relative hypoxia (7% oxygen) of a Stulberg chamber. The criteria for malignancy of these colonies was based upon cellular cytochemical staining characteristics, the presence of specific cell surface markers, and the ability of these lymphoid cells to grow without the addition of a lymphoid mitogen. With this technique, specific nutritional requirements and drug sensitivities can be established in vitro, and these data may permit tailoring of individual antileukemic therapy.

Development of a Myeloproliferative Disease or a T Cell Lymphoblastic Leukemia in a Murine Bone Marrow Transplant Model of NUP214-ABL1.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 618-618
Author(s):  
Jennifer L. Rocnik ◽  
Melanie Cornejo ◽  
Benjamin H. Lee ◽  
Rachel Okabe ◽  
Elizabeth McDowell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Flow Cytometric Analysis ◽  
Leukemic Cells ◽  
Histopathological Analysis ◽  
Myeloproliferative Disease ◽  
Marrow Cells

Abstract Leukemias are often associated with aberrant tyrosine kinase activity that occurs as a result of chromosomal translocations. These mutations are able to confer a proliferative and survival advantage to leukemic cells, as well as cooperate with other mutations that impair cell differentiation, thus leading to the development of leukemia. NUP214-ABL1 is one such recently identified fusion gene that is generated by episomal amplification. The presence of the fusion was recently identified in approximately 6% of patients with T-cell acute lymphoblastic leukemia (T-ALL). By the use of a murine retroviral bone marrow transplantation model we have demonstrated that mice transplanted with NUP214-ABL1 transduced bone marrow cells developed either a myeloproliferative disorder (MPD) with a disease latency of 70 to 118 days or a T cell lymphoblastic leukemia with a disease latency of 115 to 124 days. The myeloproliferative phenotype was characterized by splenomagaly and leukocytosis, and analysis of the histopathology revealed extramedullary hematopoiesis in the liver, lung, kidney and Peyer’s patches, and an increase of peripheral blood neutrophils. Flow cytometry of single cell suspensions from spleen and bone marrow samples of mice with a myeloproliferative phenotype demonstrated an increase of Gr-1+/Mac-1+ cells (approximately 70%). Two of the mice that were transplanted with NUP214-ABL1 transduced bone marrow cells developed T cell lymphomas that were characterized by large thymomas, a phenotype that is consistent with other models of activated tyrosine kinases over long disease latencies. Histopathological analysis of the thymi revealed effacement of normal thymic architecture as well as T cell infiltrate into the surrounding skeletal muscle. In addition, flow cytometric analysis revealed a significant increase in the CD4+/CD8+ T cell population in the thymi of these animals. No disease was observed in secondary transplant recipients following 60 days of observation. In conclusion, these results indicate that NUP214-ABL1 is able to cause either a myeloproliferative disease or a T cell lymphoma over longer latencies in mice, the latter being similar to the phenotype observed in humans with expression of the NUP214-ABL1 fusion. These findings provide a useful model for future experiments to determine if there is a contribution of other mutations together with the NUP214-ABL1 fusion towards the development of a T-ALL phenotype in mice.

Clonal Profile Analysis of Leukemic Progenitors and Diagnosis Blast Cells in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4879-4879
Author(s):  
Marinella Veltroni ◽  
Maddalena Paganin ◽  
Chiara Frasson ◽  
Giulia Fabbri ◽  
Antonio Marzollo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Gene Rearrangements ◽  
Healthy Children ◽  
Cell Precursor ◽  
Clonal Rearrangement

Abstract Recent studies suggest that the majority of malignant cells found in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) arise from a rare population of leukemic progenitors. Little information is available on the presence of clonal rearrangements in cells at the stage of early precursor. To address this issue we analyzed clonality profile of early leukemic precursors sorted by flow-cytometry. Leukemic cells were obtained from bone marrow samples collected at diagnosis from 6 patients with childhood BCP-ALL. Furthermore, bone marrow cells were collected from 3 healthy children who were harvested for bone marrow donation. Three subpopulations of leukemic cells were investigated: total unsorted blasts, the sorted CD34+/CD38−/CD19+, and the sorted CD34+/CD38−/CD19− cells. Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements were screened by polymerase chain reaction (PCR) in the sorted populations and in the bulk leukemic cells in order to identify molecular markers of clonal evolution. Sequence analysis was then performed on the N-region. Overall, a total of 38 different Ig/TCR gene rearrangements were identified in the 3 cell populations under study (total blasts, CD34+/CD38−/CD19+, and CD34+/CD38−/CD19−). Of them, 13 (34%) were found in the three populations; 12 (31%) were found in two of the three populations: 7 in total blasts and CD19+ subset, 3 in total blasts and CD19−, 2 in CD19− and CD19+; finally, 13 were found only in one subpopulation: 4 in total blast cell, 5 in CD19+, 4 in CD19−. In all the six patients studied, BCP-ALL progenitors CD34+/CD38−/CD19− and CD19+ and the bulk tumor blasts shared at least one Ig/TCR gene clonal rearrangement with the same N-region. In 5 out of 6 patients at least one rearrangement detected in the BCP-ALL progenitors was undetectable in total blasts. Conversely, in 3 patients the clonal rearrangement observed in the bulk leukemic cells was not identified in any of the two sorted ALL precursor populations. Clonal rearrangement was never detected in the samples from healthy bone marrow donors. Our findings confirm that clonal rearrangement may be detected at the stage of early B-lineage precursor CD34+/CD38−/CD19−, suggesting that leukemic transformation may occur at this stage or even before in BCP-ALL. We plan to extend this observation by repopulating studies in NOD/SCID mice.

scholarly journals Immunoglobulin gene rearrangements in remission bone marrow specimens from patients with acute lymphoblastic leukemia

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 835-838 ◽  
Author(s):  
BA Zehnbauer ◽  
DM Pardoll ◽  
PJ Burke ◽  
ML Graham ◽  
B Vogelstein
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Clinical Remission ◽  
Recombinant Dna ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Chain Gene ◽  
Immunoglobulin Gene ◽  
Marrow Cells

Abstract Recombinant DNA probes for the joining (JH) segment of the immunoglobulin heavy chain gene were used to detect molecular rearrangements of this gene in the DNA of bone marrow cells obtained during remission of acute lymphoblastic leukemia (ALL). This molecular approach was optimized and found to exceed the sensitivity of conventional morphologic screening for detecting residual leukemia cells; one leukemic cell in 500 normal nucleated bone marrow cells was easily detected using this approach. In the present study, bone marrow from three of seven patients in complete clinical remission (defined morphologically) contained leukemic cells in these proportions. This analysis may be of use in evaluating the status of clinical remission in selected ALL patients.

scholarly journals Antigenic analysis of hematopoiesis: II. Expression of human neutrophil antigens on normal and leukemic marrow cells

Blood ◽  
1984 ◽  
Vol 63 (3) ◽  
pp. 574-578
Author(s):  
LC Strauss ◽  
KM Skubitz ◽  
JT August ◽  
CI Civin
Keyword(s):  
Bone Marrow ◽  
Monoclonal Antibodies ◽  
Human Neutrophil ◽  
Bone Marrow Cells ◽  
Leukemic Cells ◽  
Antigenic Analysis ◽  
Lymphoid Leukemia ◽  
Blast Cells ◽  
Marrow Cells

The binding of five antineutrophil monoclonal antibodies AHN-1, -2, -3, -7, and -8, to normal and leukemic bone marrow cells was studied. AHN-7 bound to many granulocytic precursors, particularly myelocytes, and both lymphoid and blast cells in normal marrow, and to most but not all granulocyte-macrophage progenitors (CFC-GM). AHN-8 bound only to late (band and segmented) neutrophilic cells and not to CFC-GM. AHN-1, -2, - 3 bound to morphologically identifiable neutrophil precursors, but not to (day-14) CFC-GM. Approximately half of nonlymphoid leukemia specimens were positive with AHN-1 or AHN-7; by contrast, lymphoid leukemia specimens were rarely positive. AHN-8 was rarely found on leukemic cells. These antineutrophil antibodies appear to detect distinct granulopoietic subsets and may be useful in the analysis of hematologic differentiation and in the subclassification of leukemias.

Removal of Normal Competition Increases Proliferation of Pre-Leukemic Cells in a Mouse Model of Pre-B Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1430-1430
Author(s):  
Gregor SD Reid ◽  
David Barrett ◽  
Alix Eden Seif ◽  
Valerie I. Brown ◽  
Stephan A. Grupp
Keyword(s):  
Bone Marrow ◽  
Immune Cells ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Cell Populations ◽  
Wild Type ◽  
Abnormal Cells ◽  
Deficient Mice

Abstract Abstract 1430 Poster Board I-453 B cell precursor (BCP) acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. While the peak age of onset for this disease is 4 years, abnormal cells that will eventually give rise to disease can be detected in blood taken from patients at birth. Interestingly, similar abnormal cell populations can also be detected in blood taken at birth from many children who do not go onto develop ALL. Understanding the factors that influence the survival and expansion or elimination of these abnormal pre-leukemic cells will shed light on the process of leukemogenesis and may suggest strategies for the prevention of BCP-ALL progression. We have used a mouse model of BCP-ALL to investigate the influence of normal immune cells on the pre-leukemic population. An abnormal BCP population arises in Eμ-RET (RFP) transgenic mice during fetal development, with overt leukemia developing between 3 and 9 months of age. We show that purified BCP from bone marrow of 4-week old pre-leukemic RFP mice undergo rapid expansion when adoptively transferred into immune-deficient mice, in many cases reaching white blood cell counts of >105 (with >90% showing the abnormal BCP phenotype). Secondary and tertiary transfer of expanded BCP into immune-deficient mice again produced a severe BCP lymphoproliferative disease. Such an expansion was not observed when purified BCP were transferred into wild-type mice or when unsorted pre-leukemic RFP bone marrow was transferred into immune-deficient mice. In addition, outgrowth of the abnormal cells was significantly curtailed if the purified RFP cells were mixed with a tenfold excess of wild-type bone marrow cells prior to adoptive transfer. This inhibition of BCP outgrowth was not achieved with Rag1-deficient bone marrow cells, suggesting that competition with normal adaptive immune cells for limited growth factors may impair the expansion of RFP pre-leukemic cells. Consistent with this hypothesis, blockade of the IL-7 receptor on pre-leukemic cells abrogated their expansion following adoptive transfer. As production of IL-7 is elevated in lymphopenic settings, we evaluated the impact of T cell-depletion on pre-leukemic cells in RFP mice. Pre-leukemic cell populations were significantly elevated in the spleen (31.3% +/- 15.4 vs 9% +/- 9, p<0.01) and blood (17% +/-19.2 vs 3% +/- 4.8, p<0.05) of T cell-depleted mice compared to controls. Taken together, these results suggest that competition for growth factors such as IL-7 may be a limiting step in the early expansion of pre-leukemic cell populations and may provide a mechanistic link between immune responses and pediatric ALL through the cytokine-mediated expansion of the pre-leukemic cell pool. Disclosures No relevant conflicts of interest to declare.

The NR4A Orphan Nuclear Receptors Do Not Confer Prednisolone resistance In Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3870-3870
Author(s):  
Ingrid M. Ariës ◽  
Rosanna van den Dungen ◽  
Rob Pieters ◽  
Monique L. Den Boer
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Survival ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Orphan Nuclear Receptors ◽  
Qrt Pcr ◽  
Phase Protein

Abstract Background Resistance against the glucocorticoid prednisolone still remains an obstacle for treatment of pediatric precursor B acute lymphoblastic leukemia (BCP-ALL) at initial diagnosis and even more after relapse. The molecular mechanisms behind prednisolone resistance in pediatric BCP-ALL is poorly defined. The NR4A family, consisting of NR4A1 (Nur77), NR4A2 (Nurr1) and NR4A3 (Nor1), are orphan nuclear receptors, which antagonize the glucocorticoid receptor. We hypothesized that upregulated NR4A family expression is responsible for prednisolone resistance in BCP-ALL. Methods Newly diagnosed pediatric acute lymphoblastic leukemia patients’ cells were isolated from bone marrow aspirates and only samples with ≥ 90% leukemic blasts were used in the present study. Gene expression microarrays of 178 BCP-ALL patients tested for in vitro prednisolone resistance were analyzed with Limma R Package in the statistical environment R, version 2.15.0. Microarray expression levels were confirmed using qRT-PCR. Nur77, Nurr1 and Nor1 protein expression in primary BCP-ALL patients’ were assessed with reverse phase protein array. Leukemic patients’ cells were transfected with labeled siRNA against NR4A1, NR4A2, and NR4A3, simultaneously, or with labeled siScrl, using the transfection reagent Dharmafect 4. Hereafter, cytotoxicity to prednisolone was determined by the in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) drug-resistance assay. Furthermore, viability of transfected cells was counted by trypan blue exclusion assay and cells were harvested after 72 hours of culture for RNA and protein isolation. Knockdown was confirmed with qRT-PCR and Western blot. Results In this study of 178 precursor BCP-ALL patients we discovered a 3.0-fold (p=0.007) raise in NR4A1, NR4A2, and NR4A3 microarray mRNA expression in in vitro prednisolone resistant compared to sensitive BCP-ALL patients’ cells, which was confirmed by qRT-PCR. In addition, reverse phase protein array identified a 2.7-fold (p<0.001) increased Nurr1 (NR4A1) and Nur77 (NR4A2) protein expression in in vitro prednisolone resistant compared to sensitive BCP-ALL patients’ cells. Nurr1 and Nur77 protein levels were overall 5-fold (p<0.001) higher in BCP-ALL patients compared to normal bone marrow cells. Simultaneous siRNA mediated knockdown of Nur77, Nurr1 and Nor1 in pediatric leukemic patients’ ALL cells decreased leukemic cell survival by 25.4±11.1% (p=0.029), but did not sensitize these cells to prednisolone (n=4). Conclusion The NR4A family members are higher expressed in prednisolone resistant ALL patients’ cells. Although literature describes an antagonizing effect of the NR4A family members on the glucocorticoid receptor, we could not find a functional contribution of the NR4A family to prednisolone resistance in BCP-ALL. We furthermore discovered an increased NR4A family expression in leukemic cells of BCP-ALL patients compared to normal bone marrow cells. Targeting of NR4A genes impaired cell survival. However, compensatory mechanisms exist and consequently all three NR4A members need to be targeted simultaneously to diminish cell survival. These data therefore suggest that the NR4A genes are not suitable to reverse prednisolone resistance nor to kill leukemic cells by targeted drugs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Antigenic analysis of hematopoiesis: II. Expression of human neutrophil antigens on normal and leukemic marrow cells

Blood ◽  
1984 ◽  
Vol 63 (3) ◽  
pp. 574-578 ◽  
Author(s):  
LC Strauss ◽  
KM Skubitz ◽  
JT August ◽  
CI Civin
Keyword(s):  
Bone Marrow ◽  
Monoclonal Antibodies ◽  
Human Neutrophil ◽  
Bone Marrow Cells ◽  
Leukemic Cells ◽  
Antigenic Analysis ◽  
Lymphoid Leukemia ◽  
Blast Cells ◽  
Marrow Cells

Abstract The binding of five antineutrophil monoclonal antibodies AHN-1, -2, -3, -7, and -8, to normal and leukemic bone marrow cells was studied. AHN-7 bound to many granulocytic precursors, particularly myelocytes, and both lymphoid and blast cells in normal marrow, and to most but not all granulocyte-macrophage progenitors (CFC-GM). AHN-8 bound only to late (band and segmented) neutrophilic cells and not to CFC-GM. AHN-1, -2, - 3 bound to morphologically identifiable neutrophil precursors, but not to (day-14) CFC-GM. Approximately half of nonlymphoid leukemia specimens were positive with AHN-1 or AHN-7; by contrast, lymphoid leukemia specimens were rarely positive. AHN-8 was rarely found on leukemic cells. These antineutrophil antibodies appear to detect distinct granulopoietic subsets and may be useful in the analysis of hematologic differentiation and in the subclassification of leukemias.

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