scholarly journals Current Understandings of Myeloid Differentiation Inducers in Leukemia Therapy

2020 ◽  
pp. 1-9
Author(s):  
Shinichiro Takahashi
Keyword(s):  
Myeloid Cell ◽  
Chemotherapeutic Agents ◽  
Differentiation Therapy ◽  
New Era ◽  
Trans Retinoic Acid ◽  
Epigenetic Modifiers ◽  
All Trans Retinoic Acid ◽  
Potential Applications ◽  
Differentiation Inducers ◽  
Low Dose Cytarabine

Differentiation therapy using all-trans retinoic acid for acute promyelocytic leukemia (APL) is well established. Several attempts have been made to treat non-APL, AML patients by employing differentiation inducers, such as hypomethylating agents (HMAs), and low-dose cytarabine (Ara-C) (LDAC), with encouraging results. Other than HMAs and LDAC, various inducers of myeloid cell differentiation have been identified. This review describes and categorizes these inducers, which include glycosylation modifiers, epigenetic modifiers, vitamin derivatives, cytokines, and chemotherapeutic agents. Some of these inducers are currently being used in clinical trials. I highlight the potential applications of glycosylation modifiers and epigenetic modifiers, which are attracting increasing attention in their use as differentiation therapy against AML. Among the agents described in this review, epigenomic modifiers seem particularly promising, and particular attention should also be paid to glycosylation modifiers. These drugs may signal a new era for AML differentiation therapy.

Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome

Blood ◽  
2009 ◽  
Vol 114 (27) ◽  
pp. 5512-5521 ◽  
Author(s):  
Maaike Luesink ◽  
Jeroen L. A. Pennings ◽  
Willemijn M. Wissink ◽  
Peter C. M. Linssen ◽  
Petra Muus ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Differentiation Therapy ◽  
Chemokine Production ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Pulmonary Infiltration

Abstract In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide can induce a differentiation syndrome (DS) with massive pulmonary infiltration of differentiating leukemic cells. Because chemokines are implicated in migration and extravasation of leukemic cells, chemokines might play a role in DS. ATRA stimulation of the APL cell line NB4 induced expression of multiple CC-chemokines (CCLs) and their receptors (> 19-fold), resulting in increased chemokine levels and chemotaxis. Induction of CCL2 and CCL24 was directly mediated by ligand-activated retinoic acid receptors. In primary leukemia cells derived from APL patients at diagnosis, ATRA induced chemokine production as well. Furthermore, in plasma of an APL patient with DS, we observed chemokine induction, suggesting that chemokines might be important in DS. Dexamethasone, which efficiently reduces pulmonary chemokine production, did not inhibit chemokine induction in APL cells. Finally, chemokine production was also induced by arsenic trioxide as single agent or in combination with ATRA. We propose that differentiation therapy may induce chemokine production in the lung and in APL cells, which both trigger migration of leukemic cells. Because dexamethasone does not efficiently reduce leukemic chemokine production, pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung.

Increased Expression of Cyclin A1 mRNA Is a Novel Adverse Prognostic Indicator for Acute Promyelocytic Leukemia in Differentiation Therapy by All-Trans Retinoic Acid.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2344-2344
Author(s):  
Tsuyoshi Nakamaki ◽  
Hidetoshi Nakashima ◽  
Masamichi Hattori ◽  
Takako Usui ◽  
Mayumi Honma ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Leukocyte Count ◽  
Prognostic Indicator ◽  
Remission Induction ◽  
Differentiation Therapy ◽  
Cyclin A1 ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Cd34 Cells ◽  
Genomic Methylation

Abstract The retinoic acid syndrome (RAS) is a most important complication in all-trans retinoic acid (ATRA)-based remission induction therapy in acute promelocytic leukemia (APL). Predictive factors associated with the development of RAS have not been fully established. Cyclin A1 is a tissue specific cyclin that is required for G2/M phase transition in spermatogenesis. Abnormal expression of cyclin A1 has association with tumorigenesis. Human cyclin A1 is highly expressed in acute myeloid leukemia, especially in APL. The close association between expression of cyclin A1 and pathogenesis of APL was suggested by previous study, which showed (1) the APL-associated aberrant fusion proteins(PML-RARαor PLZF-RARα) caused overexpression of cyclin A1 mRNA through the direct activation of it’s promoter, (2) the elevation of cyclin A1 expression was reversed by treatment with ATRA in APL cells. To elucidate the clinical relevance between expression of cyclin A1 and APL, we examined expression of cyclin A1 mRNA in 37 APL samples having PML-RARα fusion gene, and correlated the results of clinical features and disease outcomes of the APL patients treated with ATRA-based differentiation therapy. Twenty-nine patients out of 37 were treated with ATRA-based remission induction therapy, including (1) ATRA(45mg/m2) followed by chemotherapy (cytarabine plus idarubicin) if the initial leukocyte count was below 3x109/L or (2) ATRA combined chemotherapy if the initial leukocyte count exceeded 3x109/L. Levels of cyclin A1 transcripts were determined by quantitative real-time RT-PCR. Cyclin A1 mRNA expression index (A1 index)was defined as copy numbers of cyclin A1 in μg RNA which contains 107 copies of GAPDH. Genomic methylation status of cyclin A1 promoter was also analyzed quantitatively using real-time PCR-based method as described previously. All APL samples expressed detectable cyclin A1 mRNA, and A1 index ranged from 4.3 to 202 (A1 index 71.9± 59.5 [mean±SD]), while CD34 +cells isolated from 4 normal bone marrow samples showed below detection levels of cyclin A1 mRNA. In APL cells, initial white blood cell count and A1 index showed significant correlation (r=0.557,p=0.0014). A1 index in 6 APL samples, which developed RAS, was significantly higher compared with those in a group without developing RAS (A1 index 101.5± 65.8 for a group with RAS vs. 72.9±60.1 for a group without RAS, p=0.015). Difference of initial white blood cell count between these 2 groups was not statistically significant (5.0±4.8x 109/L for a group with RAS vs. 9.6±20.6x109/L for a group without RAS, p=0.118). Furthermore, in a group received ATRA-based differentiation therapy, survival probability of the group with high A1 index (A1 index > 130, 9 cases) was significantly shorter compared with the group with low A1 index (A1 index < 130, 20 cases) (p=0.035). Hypermethylation of cyclin A1 promoter was detected in 4 out of 37 APL samples and the degree of CpG methylation varied from 8.6 to 85.1%. In Hela cells, 96% of sequence was methylated. No detectable genomic methylation was found in normal CD34+ cells. However, expression levels of cyclin A1 mRNA did not have significant association with detectable methylation in APL cells. (p=0.3) In summary, the present study demonstrated that increased expression of cyclin A1 mRNA in APL cells is a novel predictive factor for the development of RAS and an adverse prognostic indicator for APL in differentiation therapy by ATRA.

scholarly journals In Pursuance of Differentiation Inducers to Combat Cancer via Targeting of Abnormal Methylation Enzymes

2020 ◽  
pp. 39-47
Author(s):  
Ming C. Liau ◽  
Jai-Hyun Kim ◽  
John P. Fruehauf
Keyword(s):  
Stem Cells ◽  
Promyelocytic Leukemia ◽  
Uv Absorption ◽  
Major Focus ◽  
Active Components ◽  
Dosage Range ◽  
Telomerase Inhibitors ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Differentiation Inducers

Cell differentiation agent-2 (CDA-2) was a promising hypomethylating agent approved by the Chinese FDA for the therapy of MDS in China. The active components of CDA-2 are differentiation inducers (DIs) and differentiation helper inducers (DHIs). DIs are chemicals capable of eliminating telomerase from abnormal MEs commonly found in human cancers. The major DI of CDA-2 is an organic acid without UV absorption. Without UV absorption as a guide, it was difficult to purify the DI of CDA-2 for identification. Thus, we pursued possible candidates to function as DIs in this study. Cancer MEs become abnormal due to association with telomerase. Naturally we sought telomerase inhibitors as possible candidates of DIs. Prostaglandin E2 (PGE2) attracted our attention because it was implicated to involve in wound healing, which is a major biological mission of progenitor stem cells (PSCs) and cancer stem cells (CSCs). Eradication of CSCs has been a major focus of our studies. Besides, PGE2 fits the description of the major DI of CDA-2. Induction of terminal differentiation (TD) of HL-60 cells by NBT assay was employed to evaluate the activity of chemicals as DIs. Cell growth was based on cell numbers. All-trans retinoic acid (ATRA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) are two well known DIs. ATRA displayed a wide active dosage range from 0.2 to 4.5 µM with a maximum of inducing 89% NBT+ cells at 3 µM. TPA displayed a narrow active dosage range from 0.2 to 0.6 nM with a maximum of inducing 84% NBT+ cells at 0.4 nM. BIBR1532 and bodine were the two telomerase inhibitors studied. Both were found active as DIs. BIBR1532 was active in the dosage range from 30 to 75 µM with a maximum of inducing 86% at 63 µM. Bodine was active in the dosage range from 60 to 98 µM with a maximum of inducing 80% at 98 µM. PGE2 was active in the dosage range from 20 to 70 µM with a maximum of inducing 80% at 56 µM. DIs at dosages not active as DIs could function as effective DHIs to other DIs. RI0.5 of BIBR1532, boldine and PGE2 as DHIs were 2.02 µM, 3.11 µM, and 0.92 µM, respectively. DIs alone, no matter how effective, could not induce NBT+ cells to reach 100%. 95% (89% plus 6% of blank) was the highest value achieved by ATRA. Incomplete induction of TD was the reason for frequent recurrence when ATRA was used alone in the therapy of acute promyelocytic leukemia (APL). A combination of ATRA and a DHI could induce NBT+ cells to reach 100% to avoid recurrence.

Differentiation Therapy of Acute Promyelocytic Leukemia with Tretinoin (All-trans-Retinoic Acid)

1991 ◽  
Vol 324 (20) ◽  
pp. 1385-1393 ◽  
Author(s):  
Raymond P. Warrell ◽  
Stanley R. Frankel ◽  
Wilson H. Miller ◽  
David A. Scheinberg ◽  
Loretta M. Itri ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Differentiation Therapy ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

scholarly journals Survival Benefit of Novel Drug Combinations Using Hypomethylating Agents for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia: A Systemic Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5182-5182
Author(s):  
Pavan Tenneti ◽  
Keri R Maher ◽  
Mohamed Mokhtar Bakr ◽  
Umar Zahid ◽  
Saad Ullah Malik ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Retinoic Acid ◽  
Elderly Patients ◽  
Low Dose ◽  
Long Term Outcomes ◽  
Secondary Aml ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Low Dose Cytarabine

Abstract Background - Acute myeloid leukemia (AML) in elderly patients (>65 years) is associated with poor prognosis with median overall survival (mOS) of 6 months. Hypomethylating agents (Azacytidine (Aza) and Decitabine) are used in elderly patients who are not candidates for intensive chemotherapy. Aza has resulted in complete remission/complete remission with incomplete hematologic recovery (CR/CRi) of 18-27.8% and mOS of 10.4-24.5 months. Decitabine resulted in CR/CRi of 18-47% and mOS of 7.7-8 months. We conducted a systemic review to assess survival benefit of novel combination drug regimens (CDR) involving hypomethylating agent (HMA) in elderly patients with newly diagnosed AML. Methods - Comprehensive literature search was conducted in Medline, Embase and Cochrane database. We included phase I/II studies only that used CDR involving HMA. Results - Initial database search (since inception) lead to 975 studies. After exclusion (duplicates, case reports, relapsed/refractory AML) final analysis included 17 studies(n=540) Ten phase I/II CDR studies involving Aza (n=334) were included. The various drugs used in combination included valproic acid/all trans retinoic acid (n= 42 ,CR/CRi=26.2% mOS= 18.1 m), thalidomide (n= 14,CR/CRi= 29%, mOS= 13.2 m ), gemtuzumab ozogamicin (GO) (n= 142,CR/CRi = 35-44%, mOS= 11 m), lenalidomide (n= 45,CR/CRi=28-44% , mOS= 3-8.2 m), panobinostat (n=38,CR/CRi=10-22.4%, mOS= 8 m), midostaurin (n=12,CR/CRi=25%, mOS=6 m) , entinostat (n=18 ,CR/CRi=0% ,mOS= 6 m ), Seven phase I/II CDR studies(n=206) involving decitabine were included. Drugs used in combination included low dose cytarabine and aclarubicin (n= 85 ,CR/CRi = 64.7% , mOS= 10-12 m ), tosedostat (n=17 ,CR/CRi= 59% mOS= 11.5 m ), bexarotene(n= 4 ,CR/CRi= 0% mOS= 9.2 m), valproic acid(n= 62 ,CR/CRi= 9% mOS= 7.4m) , GO (n= 40,CR/CRi= 45% , mOS= 7m ),bortezomib (n= 10,CR/CRi= 50% ), vorinostat(n = 31,CR/CRi= 30%). Seven studies reported outcomes for patients with adverse cytogenetics separately. Of these, Aza with lenalidomide (n= 11) had a mOS of 9.5 months and with panobinostat (n=12) the overall response rate was 25% and mOS of 7 months. Similarly, decitabine with vorinostat (n = 8) and tosedostat(n =12) resulted in CR/CRi of 25% and 43% respectively. Long term outcomes for these CDR with decitabine were not reported. In two additional studies, valproic acid/all trans retinoic acid given with AZA and low dose cytarabine & aclarubicin with decitabine(p=0.023) showed poor outcome through multivariable cox model analysis. Five studies reported response rates for subgroup of patients with secondary AML using HMA. Of these, Aza with lenalidomide (n= 16) had a CR/CRi = 27% with median response duration of 21.3 weeks, a CR/CRi of 0% with entinostat (n= 18) and CR/CRi of 22% with thalidomide(n=9). Decitabine given with tosadostat (n= 10) had CR/CRi of 60% and with bortezomib(n=3) the CR/CRi was 66%. The long term outcomes were not reported for these patients. Conclusion - Novel combinations involving Aza with valproic acid/all trans retinoic acid, thalidomide, or GO showed similar CR/CRi and mOS compared to Aza alone. Tosedostat, low dose cytarabine, and aclarubicin given in combination with decitabine showed best results with superior CR/CRi and mOS compared to decitabine alone. Bexarotene with decitabine also improved mOS over decitabine alone despite lower CR/CRi. In patients with adverse cytogenetics, Aza with lenalidomide or panobinostat showed superior CR/CRi and mOS. Decitabine given with vorinostat and tosedostat also showed superior CR/CRi. In patients with secondary AML, Aza in combination with lenalidomide or thalidomide and decitabine with tosedostat or bortezomib showed superior CR/CRi. These CDR for patients with adverse cytogenetics and secondary AML need further testing in studies designed with this specific patient population in which long term outcomes are also measured. These CDR need to be evaluated in large, randomized, prospective studies to assess definitive benefit. Disclosures No relevant conflicts of interest to declare.

Curcumin Enhances Differentiation of All-Trans Retinoic Acid (ATRA)-Sensitive and ATRA-Resistant Acute Promyelocytic (APL) Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4456-4456 ◽  
Author(s):  
Ameet R. Kini ◽  
Moolky Nagabhushan ◽  
Martin S. Tallman ◽  
Shantanu Roychowdhury
Keyword(s):  
Retinoic Acid ◽  
Therapeutic Agent ◽  
Atra Treatment ◽  
Differentiation Therapy ◽  
Cd11b Expression ◽  
Nb4 Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Nbt Reduction ◽  
Therapeutic Doses

Abstract The introduction of ATRA-based differentiation therapy has significantly enhanced outcomes in patients with APL. However, retinoic acid syndrome and ATRA-resistance remain significant concerns. It would therefore be useful to develop drugs that reduce the therapeutic doses of ATRA needed, and would be effective in ATRA-resistant cases. We have shown previously that curcumin, the yellow compound isolated from spice turmeric, suppresses the initiation and promotion stages of cancer development. In the present study we evaluated whether curcumin affects differentiation of NB4 APL cells. The NB4 cells were derived from a patient with APL, and differentiate in response to ATRA, while NB4-R1 cells are resistant to ATRA. Treatment of NB4 cells with 5 μM curcumin enhanced ATRA-mediated differentiation. Differentiation was assessed by evaluating CD11b expression, nitroblue tetrazolium (NBT) reduction and by morphologic examination. This curumin-mediated enhanced differentiation was apparent at 1 μM as well as 0.1 μM of ATRA. Curcumin alone did not cause differentiation of the NB4 cells, although higher concentrations of curcumin caused apoptosis. We then examined the effect of curcumin on the ATRA-resistant NB-R1 cells. Addition of ATRA and curcumin together induced differentiation of the NB4-R1 cells, whereas either agent alone did not cause differentiation. The differentiation was characterized by increased CD11b expression, NBT reduction and the typical morphologic changes. In addition, differentiation of the NB4-R1 cells was accompanied by restoration of the PML-oncogenic domains (PODs). These results indicate that curcumin may be another unconventional therapeutic agent in APL, following the successful use of ATRA and arsenic trioxide.

Restoration of CCAAT Enhancer Binding Protein Alpha P42 Overcomes Myeloid Differentiation Block and All-Trans Retinoic Acid Resistance in Human Acute Promyelocytic Leukemia NB4-R1 Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1238-1238 ◽  
Author(s):  
Limengmeng Wang ◽  
Haowen Xiao ◽  
Xing Zhang ◽  
Weichao Liao ◽  
Shan Fu ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Morphological Changes ◽  
Promyelocytic Leukemia ◽  
Mtor Pathway ◽  
Myeloid Differentiation ◽  
Differentiation Therapy ◽  
Cd11b Expression ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract All-trans retinoic acid (ATRA) is one of the first line agents in differentiation therapy for acute promyelocytic leukemia (APL). However, drug resistance becomes a major problem which influences the efficacy of ATRA. Mechanisms of ATRA resistance are ugly needed to be identified. Here we found that expression of C/EBPα, an important transcription factor for myeloid differentiation, was significantly suppressed in ATRA resistant APL cell line NB4-R1 compared with ATRA sensitive NB4 cells. Moreover, two forms of C/EBPα were unequally suppressed in NB4-R1 cells. Suppression of the full-length form P42 was more pronounced than the truncated form P30. Inhibition of PI3K/Akt/mTOR pathway was also observed in NB4-R1 cells. Meanwhile, C/EBPα expression was reduced by PI3K inhibitor LY294002 and mTOR inhibitor RAD001 in NB4 cell, suggesting that inactivation of the PI3K/Akt/mTOR pathway was responsible for C/EBPα suppression in APL cells. Then, we restored C/EBPα P42 and P30 by lentivirus vectors in NB4-R1 cells respectively, and found C/EBPα P42, but not P30, could increase CD11b, CD14, G-CSFR and GM-CSFR expression, which indicated the occurrence myeloid differentiation. Moreover, further upregulating of CD11b expression and differential morphological changes were found in NB4-R1 cells with restored C/EBPα P42 after ATRA treatment. However, CD11b expression and differential morphological changes could not be induced by ATRA in NB4-R1 cells infected with P30 expressing or control vector. Thus, we inferred that ATRA sensibility of NB4-R1 cells was enhanced by restoration of C/EBPα P42. In addition, we used histone deacetylase inhibitor trichostatin (TSA) to restore C/EBPα expression in NB4-R1 cells. Similar enhancement of myeloid differentiation and cell growth arrest were detected. Together, this study demonstrated that suppression of C/EBPα P42 induced by PI3K/Akt/mTOR inhibition impaired the differentiation and ATRA sensibility of APL cells. Restoring C/EBPα P42 is an attractive approach for differentiation therapy in ATRA resistant APL. Disclosures No relevant conflicts of interest to declare.

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