Loss of Growth Arrest DNA Damage 45a,b (GADD45a,b) Enhances Oncogenicity in BCR/ABL-Driven Chronic Myelogenous Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3264-3264
Author(s):  
Xiaojin Sha ◽  
Dan A. Liebermann ◽  
Barbara Hoffman
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Chronic Myelogenous Leukemia ◽  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Growth Arrest ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
Myeloid Lineage ◽  
Myeloid Progenitors

Abstract 3264 Poster Board III-1 The bcr/abl oncogene causes chronic myelogenous leukemia (CML) in human. BCR/ABL induces the transformation of myeloid lineage through MAPK, JNK/SAPK, PI3K signaling pathways. Growth arrest DNA damage 45A (GADD45A) and GADD45B are upregulated during myeloid lineage terminal differentiation. They are involved in G2/M cell cycle arrest and apoptosis in response to exogenous stress stimuli through MAPK and JNK/SAPK pathways. To investigate the effect of GADD45A and GADD45B in the development of CML, syngeneic wild type lethally irradiated mice were reconstituted with wild type, gadd45a or gadd45b null myeloid progenitors transduced with a retrovirally expressed 210-kD BCR/ABL fusion oncoprotein. We found that loss of gadd45a or gadd45b accelerated the development of CML-like disease in wild type recipients. BCR/ABL transformed gadd45a or gadd45b deficient progenitor recipients exhibited a significantly accelerated kinetics of increase in the number of WBC and percentage of myeloid blasts in blood compared to mice reconstituted with the same number of wild type bone marrow cells transduced with BCR/ABL. There was also increase in the rate of accumulation of CD11b+Gr1+ cells in the bone marrow and spleen. Using in vitro and in vivo BrdU assays, enhanced proliferation capacity was observed for both BCR/ABL transduced gadd45a and gadd45b deficient myeloid progenitors. BCR/ABL transduced gadd45a and gadd45b deficient primary myeloid progenitors formed more and bigger colonies compared to BCR/ABL transformed wild type progenitors. Impaired apoptosis was showed in BCR/ABL transduced gadd45a deficient myeloid progenitors. These results indicate that both gadd45a and gadd45b function as suppressors of the development of BCR/ABL driven CML, where gadd45a appears to suppress CML via mechanism involving inhibition of cell proliferation enhancement of apoptosis, whereas gadd45b appears to only inhibit cellular proliferation. Dissecting the molecular nature of signaling paths involved in the suppressive function of gadd45a and gadd45b in BCR/ABL driven CML, as well as analysis of Gadd45 in CML patients, is underway. Disclosures: No relevant conflicts of interest to declare.

Loss of Growth Arrest DNA Damage 45b (GADD45b) Enhances Oncogenicity in BCR/ABL-Induced Chronic Myelogenous Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5337-5337
Author(s):  
Xiaojin Sha ◽  
Barbara Hoffman ◽  
Dan A. Liebermann
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Chronic Myelogenous Leukemia ◽  
Growth Arrest ◽  
Terminal Differentiation ◽  
Myelogenous Leukemia ◽  
M Cell ◽  
Cycle Arrest ◽  
Exogenous Stress ◽  
Myeloid Progenitors

Abstract Growth arrest DNA damage 45b (GADD45b) is upregulated during myeloid lineage terminal differentiation. It is also involved in G2/M cell cycle arrest and apoptosis in response to exogenous stress stimuli. To investigate the effect of GADD45b in the development of leukemia, lethally irradiated mice were reconstituted with either wildtype or gadd45b null myeloid progenitors which retrovirally expressed 210-kD BCR/ABL fusion oncoprotein. We found that both wildtype and gadd45b null myeloid progenitors expressing BCR/ABL induced chronic myelogenous leukemia (CML)-like disease between 11days to 22days after bone marrow transplantation in recipients. However, gadd45b null recipients had a shorter latency (11days–19days) compared to those of wildtypes (14days–22days). This result implies that GADD45b acts as a supressor of CML. Data will be presented on further analyzing the phenotypes of these mice.

Loss of Stress Sensor GADD45a and GADD45b Accelerates BCR-ABL-Driven Leukemogenesis Via Distinct Signaling and Cellular Pathways.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1217-1217
Author(s):  
Xiaojin Sha ◽  
Barbara Hoffman ◽  
Dan Liebermann
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Signaling Pathways ◽  
Conflicts Of Interest ◽  
Multiple Stressors ◽  
Myelogenous Leukemia ◽  
Ras Signaling ◽  
Wild Type ◽  
Cellular Pathways ◽  
Myeloid Progenitors

Abstract Abstract 1217 The bcr/abl oncogene causes chronic myelogenous leukemia (CML) in humans. BCR/ABL is known to localize to the cytoskeleton and to display a constitutively active tyrosine kinase activity that leads to the recruitment of downstream effectors of cell proliferation and survival. This is accomplished via several adapter proteins and signaling pathways, including Ras, PI3K-AKT, PkD2-NFkB and JAK-STAT5, all of which are believed to participate in the pathogenesis of CML. The complex nature of these signaling pathways and how they contribute to the initiation and progression of CML is only partially understood. The Gadd45 family of genes (Gadd45a, Gadd45b & Gadd45g) encode for small (18 kd) nuclear proteins that are rapidly induced by multiple stressors, including genotoxic and oncogenic stress. They are involved in G2/M cell cycle arrest and apoptosis in response to exogenous stress stimuli through MAPK and JNK/SAPK pathways. Furthermore Gadd45a has been identified as a mediator of oncogenic Ras signaling. GADD45 proteins are upregulated during myeloid lineage terminal differentiation. To investigate if and how GADD45A and GADD45B play a role in the development of CML, syngeneic wild type lethally irradiated mice were reconstituted with wild type, gadd45a or gadd45b null myeloid progenitors transduced with a retrovirally expressed 210-kD BCR/ABL fusion oncoprotein. It was observed that loss of gadd45a or gadd45b accelerates the development of BCR/ABL driven leukemia in wild type recipients. BCR/ABL transformed gadd45a or gadd45b deficient progenitor recipients exhibited significantly accelerated kinetics of increase in the number of WBC and percentage of myeloid blasts in blood compared to mice reconstituted with the same number of wild type bone marrow cells transduced with BCR/ABL. There was also increase in the rate of accumulation of CD11b+Gr1+ cells in the bone marrow and spleen. Using in vitro and in vivo BrdU assays, enhanced proliferation capacity was observed for BCR/ABL transduced gadd45a, but not gadd45b, deficient myeloid progenitors. However, impaired apoptosis was observed both in BCR/ABL transduced gadd45a and gadd45b deficient myeloid progenitors. These results indicate that both gadd45a and gadd45b function as suppressors of the development of BCR/ABL driven CML, where gadd45a appears to suppress CML via a mechanism involving both inhibition of cell proliferation and enhancement of apoptosis, whereas gadd45b appears to effect only apoptosis. Enhanced JNK signaling was observed in both gadd45a and gadd45b deficient progenitors, whereas enhanced p38 and AKT signaling was observed only in gadd45a deficient myeloid progenitors. Taken together, these data indicate that loss of either gadd45a or gadd45b accelerates BCR-ABL driven CML via distinct signaling and cellular pathways. Further elucidating the role Gadd45 stress sensors play in suppressing the development of leukemia should increase understanding of the molecular/cellular pathology BCR/ABL mediated leukemogenesis, and has the potential to lead to the development of new/improved modalities for treatment of leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Interleukin (IL)-1 Beta and IL-6 Activated Acute and Chronic Myelogenous Leukemia-Derived Myofibroblasts to Express Leukemia-Specific Transcripts

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5094-5094
Author(s):  
Takuji Matsuo ◽  
Haruko Tashiro ◽  
Ritsu Sumiyoshi ◽  
Tadashi Yamamoto ◽  
Kensuke Matsumoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Specific Antigen ◽  
Myelogenous Leukemia ◽  
Pcr Analysis ◽  
Fish Analysis ◽  
Rt Pcr ◽  
Single Colony

Abstract Background and Aims: We previously reported that interleukin 1-beta (IL-1-b) stimulated bone-marrow stromal myofibroblasts from normal individuals to express CD34. And, when myofibroblasts were cultured with IL-1-b and IL-6, GATA-2 and CD45 expressed. We report here that bone marrow-derived myofibroblasts from acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) patients were also activated to express leukemia-specific molecules when IL-1-b and IL-6 were added to the cultures. Materials and Methods: Bone marrow samples were collected from informed 7 AML patients (2 cases of M2 with t(8;21), 3 of M0, M2, and M7 positive for FLT-ITD mutation, 2 of Philadelphia-positive bi-phenotypic acute leukemia (Ph-AL)), and 3 CML ones, whose mononuclear cells were separated, and were cultured, split, and re-cultured for one month to eliminate non-adherent cells, vascular cells, and monocytes/macrophages to prepare myofibroblasts. The obtained cells were further cultured for one more month to obtain myofibroblasts with stably growth, and then leukemia-specific molecules (FLT3-ITD, BCR-ABL1 fusion (major and minor), RUNX1-RUNX1T1 fusion) were analyzed at DNA and RNA levels. Cells were further cultured with IL-1-b and IL-6 for two weeks, and morphological changes and expressions of specific molecules were observed. Results: When bone marrow-derived myofibroblast obtained from myeloid leukemia patients were analyzed, leukemia-specific molecules were detected at DNA levels (FISH analysis detected 0.5-5% BCR-ABL1 fusion in CML- and Ph-AL-derived myofibroblast-cultures, 1-2% RUNX1- RUNX1T1 in AML with t(8;21)-cultures, and positive FLT3-ITD mutation at genomic PCR in AML-cultures); however, RT-PCR analyses revealed that leukemia-specific transcripts were not detected in all cells. When myofibroblasts were cultured with IL-1-b and IL-6, leukemia-specific transcripts were detected with RT-PCR analysis in all cases. Also, CD45, and GATA-2 expressed in these cultures. Discussion: We reported previously that a few populations of bone marrow-derived myofibroblasts obtained from AML and CML patients expressed leukemia-specific transcripts and proteins when cultured as a separated single colony; however, when myofibroblasts were cultured not as a fractionated single colony but a whole stromal cells for a long term, expression of leukemia-specific molecules weakened and no longer confirmed. Myofibroblasts with leukemic character seem to stop their proliferation and keep dormant. One interesting point is that normal stromal myofibroblasts derived from myeloid leukemia patients can inhibit the growth of myofibroblasts that have leukemic characters. Some mechanisms may work on this observation. Also, an important issue is that myofibroblasts reportedly have an ability of antigen presentation. If some myofibroblasts can express leukemia-specific molecules as well as HLA when cultured with IL-1-b and IL-6, they can act as a leukemia-specific antigen-presenting cell. We now attempt to research this theme to develop a new cell-mediated vaccine for myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

Multiple Myeloma On Top of Chronic Myelogenous Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4457-4457
Author(s):  
Elie Chalhoub ◽  
Joseph Meouchy ◽  
Shaker R. Dakhil
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Chronic Myelogenous Leukemia ◽  
Bone Marrow Biopsy ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia

Abstract Abstract 4457 Background: The occurrence of multiple myeloma (MM) in patients with chronic myelogenous leukemia (CML) is an extremely rare event. There are only 10 cases reported in literature, with only 5 of them treated with imatinib. The longest was for 65 months. Case presentation: A 70-year-old Caucasian female presented for follow-up on her chronic myelogenous leukemia (CML). She was diagnosed 8 years prior and had a Philadelphia chromosome positive on FISH and PCR. She had been treated with Imatinib for 72 months and initially responded well, but later developed pancytopenia and hematologic and cytogenetic progression of her CML despite dose adjustments. She was switched to Nilotinib 15 months prior with partial cytogenetic response, and persistence of her pancytopenia. Her symptoms were fatigue and weight loss. She denied bleeding, fever, or back pain. Her physical exam was unremarkable. Her labs showed hemoglobin of 8.5 g/dL, WBC 2.2 K/μL with 48% segmented and platelets count of 30 K/μL. Bone marrow biopsy and aspirate showed 15–20% clustered monoclonal plasma cells and persistence of CML. Serum IgG was 2248 mg/dL with an IgG Kappa monoclonal peak on serum protein electrophoresis. A skeletal bone survey revealed no lytic lesions. Otherwise her laboratory findings were unremarkable except for a creatinine of 1.39 mg/dL and a β-2-microglobulin of 4.6 mg/L. She was diagnosed with multiple myeloma, and started on chemotherapy with bortezomib, liposomal doxorubicin, and dexamethasone. Nilotinib was held. After 4 cycles of chemotherapy, her repeat bone marrow biopsy showed partial remission of MM, and persistence of CML. Her blood counts are improving. Discussion: A PubMed review of literature shows 10 reported cases of MM occurrence in patients with CML (1974–2012). Only 5 of these cases have been on Imatinib, for a duration ranging between 7 and 65 months. There were no reports about other tyrosine kinase inhibitors (TKI). This is the first reported case of MM on top of CML while on Nilotinib, and after the longest duration on Imatinib. Conclusion: Tyrosine kinase inhibitors (TKI) constitute a revolution in the treatment of CML. With marked improvement of survival, patients are now prone to other malignancies. Reporting more cases will help understand the long term effects of TKIs. Disclosures: No relevant conflicts of interest to declare.

Angiogenic Factors in Chronic Myelogenous Leukemia: Evaluation at Diagnosis and After 3 and 6 Months of Treatment with Imatinib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2163-2163
Author(s):  
Leonardo Carvalho Palma ◽  
Nadiele Fatima de Marco Fagundes ◽  
Fabiano Pinto Saggioro ◽  
Fernando Chahud ◽  
Luciana Correa Oliveira de Oliveira ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hodgkin Lymphoma ◽  
Chronic Myelogenous Leukemia ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Angiogenic Factors ◽  
Myelogenous Leukemia ◽  
Hematologic Response ◽  
Tnf Α ◽  
Major Factors

Abstract Abstract 2163 Poster Board II-140 Background: In many cancers including chronic myelogenous leukemia (CML), an increased vascularity inside the tumor microenvironment has been showed recently, which might permit a sufficient blood delivery to the growing neoplastic cells. In fact, angiogenesis might be one of the major factors in the neoplastic process. Although many efforts have been done to elucidate the biological mechanisms of this process in CML, it has not been completely understood. Moreover, the effect of imatinib on some angiogenic factors like angiogenin, IL-6 and IL-8 is poorly known. In order to answer these two questions, we measured angiogenin, IL-6, IL-8, bFGF, TNF-α and VEGF plasma levels in CML patients at diagnosis, 3 and 6 months of imatinib therapy using cytometric bead array (CBA). Patients and methods: Bone marrow microvessel density (MVD) measured in hotspots was evaluated in 17 CML patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Plasma samples from 9 healthy volunteers and 17 CML patients at diagnosis, at 3 and 6 months of treatment (13 patients and 11 patients, respectively) were also analyzed. Results: The median MVD was higher in CML than Hodgkin Lymphoma patients (p<0.001). IL-6 and VEGF concentration were higher in CML patients than healthy controls (p=0.02, p<0.01, respectively). IL-8 tended to be higher in CML patients (p=0.06) (Figure 1). On the other hand, there was no difference in angiogenin (p=0.43), bFGF (p=0.90) and TNF-α (p=0.45). After 3 months of treatment, there was a clear decrease in IL-6, TNF-α and VEGF (All p<0.001). The reduction of IL-8 was only observed after 6 months of treatment (p=0.02). There was not any tendency of change in angiogenin and bFGF along this period of time. Although IL-6, IL-8 and TNF-α decreased in one patient, who did not achieve a hematologic response at 3 months, the VEGF plasmatic concentration did not reduce. Moreover, in another patient, who lost the hematologic response at 6 months, only VEGF increased again (Figure 2). At diagnosis, IL-6 correlated with the percentage of Philadelphia chromosome in bone marrow (r=0.85, p<0.01) and TNF-α correlated with MVD (r=0.54, p=0.03). Conclusions: We observed an increased vascularity in the bone marrow of CML patients at diagnosis. IL-6 and VEGF, which were increased at diagnosis, IL-8, which tended to be increased at diagnosis, and TNF-α, which had some correlation with MVD, seem to be involved in the pathophysiology of angiogenesis in CML. Bearing in mind the evolution of the 6 angiogenic factors as according to the hematologic response (Figure 2), VEGF might be a possible target in no-responding patients. In fact, to our knowledge, this is the first study which evaluated these 6 angiogenic factors at diagnosis and after 3 and 6 months of treatment with imatinib. Disclosures: No relevant conflicts of interest to declare.

Lymphocytes Are Dispensable In Neutrophil Homeostasis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2613-2613 ◽  
Author(s):  
Stefanie Bugl ◽  
Tina Wiesner ◽  
Lothar Kanz ◽  
Hans-Georg Kopp ◽  
Stefan Wirths
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Red Cell ◽  
Wild Type ◽  
Absolute Increase ◽  
Hematopoietic Stem ◽  
Csf Levels ◽  
Neutrophil Depletion ◽  
Peripheral Neutrophil ◽  
Myeloid Progenitors

Abstract Abstract 2613 Introduction: In contrast to red cell or platelet homeostasis, the feedback mechanisms involved in the control of peripheral neutrophil numbers are incompletely understood. Granulocyte-Colony Stimulating Factor (G-CSF) is generally accepted to be the most important determinant of neutrophil production and release from the bone marrow. Recently, a feedback loop including a specialized subset of T-lymphocytes (Tn cells) has been established to explain the correlation between peripheral neutrophil clearance and increased G-CSF production. Methods: Wild type C57bl/6 mice or NODSCIDcγ−/− received anti-Gr1 or anti-1A8 antibodies to deplete neutrophils. Hematopoietic tissues and peripheral blood were harvested at different times and analyzed on cellular, protein and RNA level. Results: Both anti-Gr1 and 1A8 antibodies reduced neutrophils effectively and persistently in vivo. The reaction on neutrophil depletion in the marrow uniformely consisted of an absolute increase in lin-/Sca1+/c-kit+ (LSK) cells and a shift of myeloid progenitors towards granulocyte-macrophage precursors (GMP) and common myeloid progenitors (CMP) at the expense of megakaryocyte-erythrocyte precursors (MEP). Of note, exogenous G-CSF resulted in identical changes. We therefore hypothesized that neutrophil depletion increases G-CSF through a feedback regulatory loop. Neutrophil depletion with anti-Gr1 antibody in wt mice increased G-CSF levels up to approximately 8-fold. While previous observations suggest that G-CSF may be passively regulated through receptor binding and internalization by mature neutrophils, we also found a 10-fold increase of G-CSF mRNA in the marrow. These findings are consistent with active feedback. Interestingly, the effects of 1A8 antibody on G-CSF were less pronounced. Instead, mice depleted of neutrophils with 1A8 antibody displayed predominant increases of M-CSF, suggesting redundant feedback pathways. Our results in wildtype mice treated with 1A8 antibody confirm previous data by Stark et al. (Immunity 2005; 22: 285–294), including increases of IL-23 and IL-17 after neutrophil depletion. However, when neutrophils were depleted in NODSCIDcγ−/− mice, who lack lymphocytes and NK-cells, both IL-23 and IL-17 remained unchanged, but G-CSF levels still increased markedly. Conclusions: Effective neutrophil depletion by antibodies directed against different neutrophil antigens uniformly results in major shifts in the hematopoietic bone marrow showing an increase in the number of LSK hematopoietic stem cells accompanied by a significant increase in myeloid progenitors at the expense of thrombopoietic, red cell, and lymphoid precursors. Our results demonstrate regulatory feedback loops of neutrophil granulopoiesis culminating in increased production of myelopoiesis stimulating cytokines such as G-CSF, GM-CSF, and M-CSF. The underlying chain of events includes IL-23 and IL-17 in wild type mice as previously described. However, additional redundant pathways exist in lymphocytopenic NODSCIDcγ−/− mice. Disclosures: No relevant conflicts of interest to declare.

Chaetocin Anti-Leukemia Activity Against Chronic Myelogenous Leukemia Stem Cells Is Potentiated By Bone Marrow Stromal Factors and Overcomes Innate Imatinib Resistance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4517-4517
Author(s):  
Luke Truitt ◽  
Catherine Hutchinson ◽  
Karen Mochoruk ◽  
John F. DeCoteau ◽  
C. Ronald Geyer
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Colony Formation ◽  
Conflicts Of Interest ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Innate Resistance ◽  
Tki Resistance

Abstract Chronic myelogenous leukemia (CML) is maintained by a minor population of leukemic stem cells (LSCs) that exhibit innate resistance to tyrosine kinase inhibitors (TKIs) targeting BCR-ABL. Innate resistance can be induced by cytokines and growth factors secreted by bone marrow stromal cells (BMSFs) that protect CML-LSCs from TKIs, resulting in minimal residual disease. Developing therapies that can be combined with TKIs to eradicate TKI-insensitive CML-LSCs, is critical for disrupting innate TKI resistance and preventing disease relapse. Cancer cells balance reactive oxygen species (ROS) and antioxidants at higher than normal levels, which promotes their proliferation and survival, but also makes them susceptible to damage by ROS-generating agents. BCR-ABL expression increases cellular ROS levels, whereas, TKI inhibition of BCR–ABL reduces ROS. Furthermore, BMSFs, which are implicated in innate TKI resistance, can increase ROS levels in CML cells. Thus, we postulated that BMSF mediated increases in ROS might enhance triggering of ROS-mediated damage in TKI treated CML-LSCs by chaetocin, a mycotoxin with anticancer properties that imposes oxidative stress by inhibiting thioredoxin reductase-1. To investigate chaetocin effects on innate TKI resistance, we first compared its activity with imatinib against TonB210, a murine hematopoietic cell line with inducible BCR-ABL expression, in response to BMSFs. Imatinib did not affect the growth of BCR-ABL(-) TonB210 cells but suppressed BCR-ABL(+) Ton-B210 growth, and BMSFs protected against imatinib growth suppression. In contrast, chaetocin significantly suppressed the growth of both BCR-ABL(-) and BCR-ABL(+) TonB210 cells, and these effects were potentiated by BMSFs. We then compared the effects of chaetocin as a single agent, and in combination with imatinib, on the growth of CML-LSCs derived from an established murine retroviral transduction/transplantation model of CML blast crisis, in response to BMSFs. The presence of BMSFs reduced cytotoxicity and apoptosis induction by imatinib, but potentiated these effects in chaetocin treated CML-LSCs. Colony formation by CML-LSCs was significantly inhibited by treatment with either imatinib or chaetocin. However, BMSFs conferred significant protection from colony inhibition by imatinib, whereas, no colony formation was observed in cells exposed to chaetocin and BMSFs. Both BMSFs and chaetocin increased ROS in CML-LSCs and the addition of BMSFs and chaetocin resulted in significantly higher levels compared to chaetocin or BMSFs alone. Pretreatment of CML-LSCs with the anti-oxidant N-acetyl-cysteine blocked chaetocin cytotoxicity, even in the presence of BMSFs. Chaetocin effects on CML-LSC self-renewal in vivo were assessed by transplanting CML-LSCs into secondary recipients following in vitro exposure to chaetocin, in the presence or absence of BMSFs. Disease latency in mice transplanted with CML-LSCs following chaetocin treatment more than doubled compared to mice transplanted with untreated CML-LSCs or CML-LSCs exposed to BMSFs. Mice transplanted with CML-LSCs following chaetocin treatment in the presence of BMSFs had significantly extended survival time compared to mice transplanted with CML-LSCs treated with chaetocin alone. Our findings indicate that chaetocin activity against leukemia initiating cells is significantly enhanced in the presence of BMSFs and suggest that chaetocin may be effective as a co-drug to complement TKIs in CML treatment by disrupting the innate resistance of CML-LSCs through an ROS dependent mechanism. Disclosures No relevant conflicts of interest to declare.

Philadelphia chromosome and terminal transferase-positive acute leukemia: similarity of terminal phase of chronic myelogenous leukemia and de novo acute presentation.

1983 ◽  
Vol 1 (11) ◽  
pp. 669-676 ◽  
Author(s):  
K Jain ◽  
Z Arlin ◽  
R Mertelsmann ◽  
T Gee ◽  
S Kempin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Leukocyte Antigen ◽  
Terminal Transferase

Twenty-eight patients with Philadelphia chromosome (Ph1)--positive and terminal transferase (TdT)--positive acute leukemia (AL) were treated with intensive chemotherapy used for adult acute lymphoblastic leukemia (L-10 and L-10M protocols). Fifteen patients had a documented chronic phase of Ph1-positive chronic myelogenous leukemia preceding the acute transformation (TdT + BLCML) while the remaining 13 patients did not (TdT + Ph1 + AL). An overall complete remission (CR) rate of 71% was obtained with a median survival of 13 months in the responders. Clinical presentation, laboratory data, cytogenetics, response to treatment, and survivals of the two groups of patients are compared. These results appear to be similar, suggesting a common or closely related origin. Since the overall survival of those receiving chemotherapy maintenance is poor, three patients underwent allogeneic bone marrow transplantation (BMT) from histocompatibility leukocyte antigen--matched siblings after they achieved CR. One of them is a long-term survivor (35 + months) with a Ph1-negative bone marrow. New techniques such as BMT should be considered in young patients with a histocompatibility leukocyte antigen--compatible sibling once a CR has been achieved.

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