Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib

We describe an approach to inhibit chemotherapy-induced myelosuppression. We found that short-term exposure of mice to the FLT3 inhibitor quizartinib induced the transient quiescence of multipotent progenitors (MPPs). This property of quizartinib conferred marked protection to MPPs in mice receiving fluorouracil or gemcitabine. The protection resulted in the rapid recovery of bone marrow and blood cellularity, thus preventing otherwise lethal myelosuppression. A treatment strategy involving quizartinib priming that protected wild-type bone marrow progenitors, but not leukemic cells, from fluorouracil provided a more effective treatment than conventional induction therapy in mouse models of acute myeloid leukemia. This strategy has the potential to be extended for use in other cancers where FLT3 inhibition does not adversely affect the effectiveness of chemotherapy. Thus, the addition of quizartinib to cancer treatment regimens could markedly improve cancer patient survival and quality of life.

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Molecular analysis of relapse in chronic myeloid leukemia after allogeneic bone marrow transplantation

Blood ◽

10.1182/blood.v70.3.873.873 ◽

1987 ◽

Vol 70 (3) ◽

pp. 873-876 ◽

Cited By ~ 12

Author(s):

TS Ganesan ◽

GL Min ◽

JM Goldman ◽

BD Young

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Chronic Myeloid Leukemia ◽

Marrow Transplantation ◽

Myeloid Leukemia ◽

Allogeneic Bone Marrow Transplantation ◽

Allogeneic Bone Marrow ◽

Leukemic Cells ◽

Allogeneic Bone ◽

Leukemic Clone

Abstract Four patients with Philadelphia (Ph′) positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone.

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Molecular analysis of relapse in chronic myeloid leukemia after allogeneic bone marrow transplantation

Blood ◽

10.1182/blood.v70.3.873.bloodjournal703873 ◽

1987 ◽

Vol 70 (3) ◽

pp. 873-876

Author(s):

TS Ganesan ◽

GL Min ◽

JM Goldman ◽

BD Young

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Chronic Myeloid Leukemia ◽

Marrow Transplantation ◽

Myeloid Leukemia ◽

Allogeneic Bone Marrow Transplantation ◽

Allogeneic Bone Marrow ◽

Leukemic Cells ◽

Allogeneic Bone ◽

Leukemic Clone

Four patients with Philadelphia (Ph′) positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone.

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Effect of Short-Term Exposure to High Particulate Levels on Cough Reflex Sensitivity in Healthy Tourists: A Pilot Study

The Open Respiratory Medicine Journal ◽

10.2174/1874306401610010096 ◽

2016 ◽

Vol 10 (1) ◽

pp. 96-104 ◽

Cited By ~ 5

Author(s):

Ryuhei Sato ◽

Peijun Gui ◽

Kumiko Ito ◽

Masahiro Kohzuki ◽

Satoru Ebihara

Keyword(s):

Quality Of Life ◽

Pulmonary Function ◽

Vital Capacity ◽

Airborne Particulate Matter ◽

Forced Expiratory Volume ◽

Short Term ◽

Cough Reflex ◽

Short Term Exposure ◽

Related Quality

Background: Previous studies have reported a relationship between particulate air pollution and respiratory symptoms or decline in lung function, but information about acute effects of short-term exposure to airborne particulate matter (PM) on cough and pulmonary function is scarce. Objective: To investigate the effect of short-term exposure to high concentrations of PM on the cough reflex threshold, urge-to-cough, pulmonary function, and cough-related quality of life in a group of healthy non-resident volunteers visiting Beijing, China. Methods: Seventeen healthy residents of Sendai, Japan, who planned to attend a meeting in Beijing, were recruited. We checked local air quality and measured cough reflex thresholds, urge-to-cough, pulmonary function, and Leicester Cough Questionnaire-acute (LCQ-acute) scores in the volunteers before, during, and after their trip to Beijing. Results: The PM2.5 and PM10 concentrations in Beijing were significantly higher than those in Japan on the measurement days. Cough reflex thresholds, expressed as nebulized citric acid concentrations required to induce ≥ 2 and ≥ 5 coughs, were significantly lower during the stay in Beijing than before or after the visit. Vital capacity, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC were significantly lower during the stay in Beijing than before the trip. Similarly, the urge-to-cough threshold was significantly lower during the stay in Beijing than after the trip, as was the total LCQ-acute score. Conclusion: We tentatively concluded that short-term exposure to high PM concentrations may have adverse effects on cough reflex and urge-to-cough thresholds, pulmonary function, and cough-related quality of life.

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Human acute myeloid leukemia cells bind to bone marrow stroma via a combination of beta-1 and beta-2 integrin mechanisms

Blood ◽

10.1182/blood.v82.10.3125.3125 ◽

1993 ◽

Vol 82 (10) ◽

pp. 3125-3132 ◽

Cited By ~ 65

Author(s):

LJ Bendall ◽

K Kortlepel ◽

DJ Gottlieb

Keyword(s):

Bone Marrow ◽

Extracellular Matrix ◽

Acute Myeloid Leukemia ◽

Cell Adhesion ◽

Myeloid Leukemia ◽

Extracellular Matrix Proteins ◽

Matrix Proteins ◽

Leukemic Cells ◽

Beta 2 ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) cells respond to exogenous stimulation from myeloid growth factors that may be secreted by cells of the bone marrow (BM) stroma and retained by glycosaminoglycans in the extracellular matrix. We have analyzed the capacity of malignant cells from patients with AML to maintain close proximity to sites of growth factor production and retention by binding to BM stromal elements, including fibroblasts and extracellular matrix proteins. Leukemic cells from all cases of AML adhered to BM fibroblast (BMF) monolayers (mean +/- standard error [SE] percentage binding, 30.9% +/- 2.5%; n = 23) and to fibronectin and laminin (mean +/- SE percentage binding, 28.0% +/- 4.1% [n = 11] and 21.5% +/- 2.3% [n = 8], respectively). Binding to bovine and human collagen type 1, vitronectin, hyaluronic acid, and albumin was minimal. Analysis of binding mechanisms indicated that very late antigen-4 (VLA-4) and VLA-5 were responsible for AML cell binding to fibronectin. Binding to laminin could be inhibited by antibody to the alpha chain of VLA-6. In contrast, AML cell adhesion to BMF monolayers was not impaired by blocking antibodies to either beta 1 or beta 2 integrins used alone, although the combination of anti-CD11/CD18 and anti-VLA-4 inhibited binding in more than 50% of cases. When anti- VLA-5 was added in these cases, mean +/- SE inhibition of binding of 45.5% +/- 9.1% (P < .001) was observed. Binding of AML cells to extracellular matrix proteins fibronectin and laminin is predominantly beta 1-integrin-dependent, but AML cell adhesion to BMF relies on the simultaneous involvement of beta 1 and beta 2 integrins as well as other currently unrecognized ligands.

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Granulocytic Sarcoma of the Stomach Presenting as Dysphagia during Pregnancy

Case Reports in Gastrointestinal Medicine ◽

10.1155/2011/627549 ◽

2011 ◽

Vol 2011 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

Anuradha Sekaran ◽

Santosh Darisetty ◽

Sandeep Lakhtakia ◽

Mohan Ramchandani ◽

Duvuru Nageshwar Reddy

Keyword(s):

Bone Marrow ◽

Myeloid Leukemia ◽

Gastric Lesion ◽

Granulocytic Sarcoma ◽

Leukemic Cells ◽

Upper Gi ◽

Upper Gi Endoscopy ◽

Nodular Lesions ◽

Progressive Dysphagia ◽

Acute Myeloid

Granulocytic sarcoma also known as extramedullary myeloid sarcoma or chloroma is an uncommon manifestation of leukemia and presents as a deposit of leukemic cells outside the bone marrow. We report a case of a twenty-five-year-old pregnant woman who presented with progressive dysphagia and recurrent postprandial vomiting. Upper GI endoscopy had shown large flat laterally spread nodular lesions in the cardia and proximal body of stomach. Biopsies from the gastric lesion showed granulocytic sarcoma of the stomach. Concurrent peripheral and bone marrow picture was suggestive of acute myeloid leukemia (AML–M4). There is limited reported literature on granulocytic sarcoma of the stomach. Concurrent gastric granulocytic sarcoma involving cardia and AML in pregnancy has not been reported till date.

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Acute myeloid leukemia M4 with bone marrow eosinophilia (M4Eo) and inv(16)(p13q22) exhibits a specific immunophenotype with CD2 expression

Blood ◽

10.1182/blood.v81.11.3043.3043 ◽

1993 ◽

Vol 81 (11) ◽

pp. 3043-3051 ◽

Cited By ~ 84

Author(s):

HJ Adriaansen ◽

PA te Boekhorst ◽

AM Hagemeijer ◽

CE van der Schoot ◽

HR Delwel ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Low Frequency ◽

Leukemic Cell ◽

Leukemic Cells ◽

Terminal Deoxynucleotidyl Transferase ◽

Cell Populations ◽

Spontaneous Proliferation ◽

Acute Myeloid

Abstract Extensive immunologic marker analysis was performed to characterize the various leukemic cell populations in eight patients with inv(16)(p13q22) in association with acute myeloid leukemia with abnormal bone marrow eosinophilia (AML-M4Eo). The eight AML cases consisted of heterogeneous cell populations; mainly due to the presence of multiple subpopulations, which varied in size between the patients. However, the immunophenotype of these subpopulations was comparable, independent of their relative sizes. Virtually all AML-M4Eo cells were positive for the pan-myeloid marker CD13. In addition, the AML were partly positive for CD2, CD11b, CD11c, CD14, CD33, CD34, CD36, CDw65, terminal deoxynucleotidyl transferase (TdT), and HLA-DR. Double immunofluorescence stainings demonstrated coexpression of the CD2 antigen and myeloid markers and allowed the recognition of multiple AML subpopulations. The CD2 antigen was expressed by immature AML cells (CD34+, CD14-) and more mature monocytic AML cells (CD34-, CD14+), whereas TdT expression was exclusively found in the CD34+, CD14- cell population. The eight AML-M4Eo cases not only expressed the CD2 antigen, but also its ligand CD58 (leukocyte function antigen-3). Culturing of AML-M4Eo cell samples showed a high spontaneous proliferation in all three patients tested. Addition of a mixture of CD2 antibodies against the T11.1, T11.2, and T11.3 epitopes diminished cell proliferation in two patients with high CD2 expression, but no inhibitory effects were found in the third patient with low frequency and low density of CD2 expression. These results suggest that high expression of the CD2 molecule in AML-M4Eo stimulates proliferation of the leukemic cells, which might explain the high white blood cell count often found in this type of AML.

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Monocytic Maturation Induced by FLT3 Inhibitor Therapy of Acute Myeloid Leukemia: Morphologic and Immunophenotypic Characteristics

Laboratory Medicine ◽

10.1093/labmed/lmz094 ◽

2019 ◽

Vol 51 (5) ◽

pp. 478-483

Author(s):

Cade D Arries ◽

Sophia L Yohe

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Tyrosine Kinase ◽

Cell Population ◽

Myeloid Leukemia ◽

Inhibitor Therapy ◽

Molecular Abnormalities ◽

Flt3 Inhibitor ◽

Flt3 Inhibitors ◽

Acute Myeloid

Abstract Background FMS-like tyrosine kinase-3 (FLT3-ITD) mutations are some of the most common mutations in acute myeloid leukemia (AML), and patient outcomes have improved since the advent of tyrosine kinase inhibitors. First, granulocytic differentiation was described in FLT3-positive AML treated with FLT3 inhibitors, and more recently, monocytic differentiation was reported. Methods Two patients with myelomonocytic cells in their bone marrow were identified during routine follow-up after AML treatment that included FLT3 inhibitors. The bone marrow study was done as standard of care. Results Both patients had FLT3-ITD+ AML and showed an atypical maturing monocytic cell population and a decrease in the leukemic blast cell population after FLT3 inhibitor therapy. Concurrent genetic testing revealed persistent genetic abnormalities. Conclusions These cases illustrate monocytic maturation in FLT3+ AML after FLT3 inhibitor treatment. It is critical for pathologists and clinicians to be aware of the differentiation phenomenon, as these patients have persistent molecular abnormalities despite response to treatment and normalization of blast counts.

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In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo

Blood ◽

10.1182/blood.v100.13.4622 ◽

2002 ◽

Vol 100 (13) ◽

pp. 4622-4628 ◽

Cited By ~ 100

Author(s):

Gunter Schuch ◽

Marcelle Machluf ◽

Georg Bartsch ◽

Masashi Nomi ◽

Henri Richard ◽

...

Keyword(s):

Bone Marrow ◽

Vascular Endothelial Growth Factor ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Leukemic Cells ◽

Vascular Endothelial ◽

Neuropilin 1 ◽

Endothelial Growth Factor ◽

Acute Myeloid

Recent findings implied that the progression of hematologic malignancies, like that of solid tumors, is dependent on neovascularization. Recent studies on patients with acute myeloid leukemia (AML) showed increased levels of leukocyte-associated vascular endothelial growth factor (VEGF) and neovascularization of the bone marrow. Murine (32D, M1) and human (HEL, U937, and UKE-1) leukemic cell lines and freshly isolated leukemic cells were analyzed for the expression of VEGF and VEGF receptor mRNA. The expression of VEGF and VEGF receptors KDR and neuropilin-1 (NRP-1) was detected in these cells. In a murine chloroma model, delivery of VEGF165using microencapsulation technology resulted in enhanced tumor growth and vascularization, whereas treatment with a VEGF antagonist soluble NRP-1 (sNRP-1) inhibited tumor angiogenesis and growth. In a systemic leukemia model, survival of mice injected with adenovirus (Ad) encoding for Fc-sNRP-1 (sNRP-1 dimer) was significantly prolonged as compared with mice injected with Ad-LacZ. Further analyses showed a reduction in circulating leukemic cells and infiltration of liver and spleen as well as bone marrow neovascularization and cellularity. Taken together, these results demonstrate that angiogenic factors such as VEGF promote AML progression in vivo. The use of VEGF antagonists as an antiangiogenesis approach offers a potential treatment for AML. Finally, our novel in vivo drug delivery model may be useful for testing the activities of other peptide antiangiogenic factors.

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Progenitor cell hyperplasia with rare development of myeloid leukemia in interleukin 11 bone marrow chimeras.

Journal of Experimental Medicine ◽

10.1084/jem.178.4.1175 ◽

1993 ◽

Vol 178 (4) ◽

pp. 1175-1188 ◽

Cited By ~ 43

Author(s):

R G Hawley ◽

A Z Fong ◽

B Y Ngan ◽

V M de Lanux ◽

S C Clark ◽

...

Keyword(s):

Bone Marrow ◽

Myeloid Leukemia ◽

Progenitor Cell ◽

Bone Marrow Cells ◽

Leukemic Cells ◽

Cell Hyperplasia ◽

Primary Host ◽

Cell Content ◽

Continuous Growth ◽

Interleukin 11

Post 5-fluorouracil-treated murine bone marrow cells infected with a recombinant retrovirus (murine stem cell virus-interleukin 11 [MSCV-IL-11]) bearing a human IL-11 gene were transplanted into lethally irradiated syngeneic mice. Analysis of proviral integration sites in DNA prepared from hematopoietic tissues and purified cell populations of long-term reconstituted primary and secondary recipients demonstrated polyclonal engraftment by multipotential stem cells. High levels (100-1,500 U/ml) of IL-11 were detected in the plasma of the MSCV-IL-11 mice. Systemic effects of chronic IL-11 exposure included loss of body fat, thymus atrophy, some alterations in plasma protein levels, frequent inflammation of the eyelids, and often a hyperactive state. A sustained rise in peripheral platelet levels (approximately 1.5-fold) was seen throughout the observation period (4-17 wk). No changes were observed in the total number of circulating leukocytes in the majority of the transplanted animals (including 10 primary and 18 secondary recipients) despite a > 20-fold elevation in myeloid progenitor cell content in the spleen. The exceptions were members of one transplant pedigree which presented with myeloid leukemia during the secondary transplant phase. A clonal origin of the disease was determined, with significant expansion of the MSCV-IL-11-marked clone having occurred in the spleen of the primary host. Culturing of leukemic spleen cells from a quaternary recipient led to the establishment of a permanent cell line (denoted PGMD1). IL-11-producing PGMD1 myeloid leukemic cells are dependent on IL-3 for continuous growth in vitro and they differentiate into granulocytes and macrophages in response to granulocyte/macrophage colony-stimulating factor. The inability of autogenously produced IL-11 to support autonomous growth of PGMD1 cells argues against a mechanism of transformation involving a classical autocrine loop.

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Far from Health: The Bone Marrow Microenvironment in AML, A Leukemia Supportive Shelter

Children ◽

10.3390/children8050371 ◽

2021 ◽

Vol 8 (5) ◽

pp. 371

Author(s):

Stephanie Sendker ◽

Katharina Waack ◽

Dirk Reinhardt

Keyword(s):

Bone Marrow ◽

Myeloid Leukemia ◽

Bone Marrow Microenvironment ◽

Leukemic Cells ◽

Therapeutic Approaches ◽

Complex Interplay ◽

Comprehensive Overview ◽

Future Challenges ◽

Cellular Components

Acute myeloid leukemia (AML) is the second most common leukemia among children. Although significant progress in AML therapy has been achieved, treatment failure is still associated with poor prognosis, emphasizing the need for novel, innovative therapeutic approaches. To address this major obstacle, extensive knowledge about leukemogenesis and the complex interplay between leukemic cells and their microenvironment is required. The tremendous role of this bone marrow microenvironment in providing a supportive and protective shelter for leukemic cells, leading to disease development, progression, and relapse, has been emphasized by recent research. It has been revealed that the interplay between leukemic cells and surrounding cellular as well as non-cellular components is critical in the process of leukemogenesis. In this review, we provide a comprehensive overview of recently gained knowledge about the importance of the microenvironment in AML whilst focusing on promising future therapeutic targets. In this context, we describe ongoing clinical trials and future challenges for the development of targeted therapies for AML.

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