News Update on Promyelocytic Leukemia Research: April – 2019

FLT3-ITD impedes retinoic acid, but not arsenic, responses in murine acute promyelocytic leukemias

Acute promyelocytic leukaemia (APL) is commonly related to activating FLT3 communication mutations. These are extremely associated with hyperleukocytosis, a serious adverse risk issue with chemotherapy-based regimens. APL may be a model for oncogene-targeted therapies: all-trans retinoic acid (ATRA) and arsenic each target and degrade its ProMyelocytic Leukemia/Retinoic Acid Receptor α (PML/RARA) driver. The combined ATRA/arsenic program currently cures nearly all patients with standard-risk APL. though FLT3-internal cycle duplication (ITD) was Associate in Nursing adverse risk issue for historical ATRA/chemotherapy regimens, the molecular bases for this result stay unknown. victimization mouse APL models, we have a tendency to unexpectedly demonstrate that FLT3-ITD severely blunts ATRA response. Remarkably, though the transcriptional output of initial ATRA response is unaffected, ATRA-induced PML/RARA degradation is dulled, as is PML nuclear body reformation and activation of P53 communication. Critically, the mix of ATRA and arsenic absolutely rescues therapeutic response in FLT3-ITD APLs, restoring PML/RARA degradation, PML nuclear body reformation, P53 activation, and APL wipeout. Moreover, arsenic targeting of traditional PML additionally contributes to APL response in vivo. These sudden results make a case for the less favorable outcome of FLT3-ITD APLs with ATRA-based regimens, and stress the key role of PML nuclear bodies in APL wipeout by the ATRA/arsenic combination. [1]

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells

Piplartine (piperlongumine) may be a plant-derived compound found in some Piper species that became a unique potential antineoplastic agent. within the gift study, we have a tendency to synthesized a unique Pt complicated containing a piplartine spinoff cis-[PtCl(PIP-OH)(PPh3)2]PF6 (where, PIP-OH = piplartine demethylated derivative; and PPh3 = triphenylphosphine) with increased toxicity in numerous cancer cells, and investigated its apoptotic action in human promyelocytic cancer HL-60 cells. The structure of PIP-OH matter was characterised by X-ray crystallographic analysis and therefore the ensuing Pt complicated was characterized by infrared, molar electrical phenomenon measurements, elemental analysis and magnetic resonance experiments. we have a tendency to found that the complicated is less assailable than piplartine in an exceedingly panel of neoplastic cell lines. Apoptotic cell morphology, exaggerated internucleosomal polymer fragmentation, while not cell wall porosity, loss of the mitochondrial transmembrane potential, exaggerated phosphatidylserine externalization and caspase-3 activation were discovered in complex-treated HL-60 cells. Treatment with the complicated additionally caused a marked increase within the production of reactive O species (ROS), and therefore the pretreatment with N-acetyl-L-cysteine, AN inhibitor, reduced the complex-induced necrobiosis, indicating activation of ROS-mediated necrobiosis pathway. Important, pretreatment with a p38 MAPK matter (PD 169316) and MKO inhibitor (U-0126), celebrated to inhibit ERK1/2 activation, additionally prevented the complex-induced necrobiosis. The complicated didn’t induce polymer time interval in acellular DNA assays. lastly, the complicated exhibits less assailable toxicity than piplartine in an exceedingly panel of various cancer cells and triggers ROS/ERK/p38-mediated necrobiosis in HL-60 cells. [2]

Establishment of a ΔF508-CF promyelocytic cell line for cystic fibrosis research and drug screening

Cystic fibrosis (CF), one in every of the foremost common genetic disorders, is caused by mutations within the CF transmembrane electrical phenomenon regulator (CFTR) sequence. In spite of serious improvement in patient life, the sickness remains deadly and incurable. Clinically, CF respiratory organ sickness claims the foremost morbidity and mortality, characterised by chronic microorganism infection, persistent neutrophilic inflammation, and pussy little airway obstruction. though of these manifestations are extremely related to neutrophils, the particular role of this scavenger cell within the sickness pathological process has not been absolutely appreciated. one in every of the key obstacles obstructive such progress is that the lack of CF neutrophile cell lines. Taking advantage of the new CRISPR/Cas9 gene-editing technology, we’ve generated a homozygous ΔF508-CF promyelocytic cell line from HL-60 cells, from that unlimited CF neutrophile cells are often differentiated. The derived cells showed defective CFTR presentation, deficient phagosomal acid (HOCl) production, and compromised microorganism killing. Such a makeup recapitulates that of primary neutrophils from CF patients. Thus, the established human CF promyelocytic cell line ought to be a useful gizmo for future CF basic analysis and drug screening. [3]

Basophil-lineage commitment in acute promyelocytic leukemia predicts for severe bleeding after starting therapy

Severe injury events occur in a very important fraction of acute promyelocytic cancer patients, either at presentation and/or early once beginning medical aid, resulting in treatment failure and early deaths. However, identification of freelance predictors for bad of severe injury at diagnosing, remains a challenge. Here, we have a tendency to investigated the immunophenotype of bone marrow leukemic cells from 109 fresh diagnosed acute promyelocytic cancer patients, notably specializing in the identification of basophil-related options, and their potential association with severe injury episodes and patient overall survival.

From all phenotypes investigated on leukemic cells, expression of the CD203c and/or CD22 basophil-associated markers showed the strongest association with the prevalence and severity of injury (p ≤ 0.007); furthermore, aberrant expression of CD7, coexpression of CD34+/CD7+ and lack of CD71 was conjointly a lot of ofttimes found among patients with (mild and severe) injury at baseline and/or once beginning treatment (p ≤ 0.009). statistical method showed that CD203c [removed]hazard ratio: twenty six.4; p = 0.003) and older age (hazard ratio: five.4; p = 0.03) were the most effective freelance predictors for additive incidence of severe injury once beginning medical aid. additionally, CD203c expression on leukemic cells (hazard ratio: four.4; p = 0.01), low factor I levels (hazard ratio: eight.8; p = 0.001), older age (hazard ratio: nine.0; p = 0.002), and high white blood corpuscle count (hazard ratio: five.6; p = 0.02) were the foremost informative freelance predictors for overall survival.

In summary, our results show that the presence of basophil-associated makeup characteristics on leukemic cells from acute promyelocytic cancer patients at diagnosing may be a powerful freelance predictor for severe injury and overall survival, which could contribute within the future to (early) risk-adapted medical aid selections. [4]

Screening of Fifteen Mangrove Plants Found in Sri Lanka for in-vitro Cytotoxic Properties on Breast (MCF-7) and Hepatocellular Carcinoma (HepG2) Cells

Aims: analysis of cytotoxic potential on the leaves and stem bark extracts of fifteen angiospermous tree plants fully grown in Ceylon on carcinoma (MCF -7) and malignant hepatoma (HepG2) cells.

Place and length of Study: At the Institute of organic chemistry, biology and Biotechnology, University of national capital between first of Gregorian calendar month 2014 to April 2015.

Methodology: Leaves and stem barks of fifteen angiospermous tree plants were extracted with solvent, chloroform, ester and wood spirit. ensuing extracts were screened for cytotoxic activity against MCF-7 and HepG2 cells victimization the Sulforhodamine B (SRB) assay.

Results: Phoenix paludosa, tree and Scyphiphora hydrophyllacea showed highest cytotoxic properties on cancer cells. Chloroform extract of stem bark of S. hydrophyllacea, Bruguiera gymnorrhiza (chloroform, ester and wood spirit extracts of leaves), solvent and ester extracts of leaves of asterid dicot genus corniculatum, wood spirit extracts of leaves and stem bark of Nipa fruticans and genus Rhizophora mucronata, wood spirit extract of stem bark of Sonneratia alba and genus Rhizophora apiculata and methanol extract of bark of A. officinalis exerted selective toxicity to HepG2 cells. The solvent extract of leaves of B. gymnorrhiza, chloroform extract of leaves of N. fruticans, ester extract of stem bark of Lumnitzera littorea, chloroform extract of leaves of genus Rhizophora apiculata and chloroform extract of leaves of Pemphis acidula showed selective cytotoxic effects against MCF-7 cells. Out of the 116 angiospermous tree extracts tested, eighty two extracts showed no important cytotoxic effects (IC50>100 µg/mL) against MCF seven or HepG2 cells.

Conclusion: The cytotoxic activities incontestable  by a number of the solvent extracts of some angiospermous tree plants offer scientific proof for his or her therapeutic potentials and more studies are required to spot active compounds accountable for cytotoxic effects. [5]

Reference

[1] Esnault, C., Rahmé, R., Rice, K.L., Berthier, C., Gaillard, C., Quentin, S., Maubert, A.L. and Kogan, S., 2019. FLT3-ITD impedes retinoic acid, but not arsenic, responses in murine acute promyelocytic leukemias. Blood, 133(13), pp.1495-1506. (Web Link)

[2] Oliveira, M.D.S., Barbosa, M.I., de Souza, T.B., Moreira, D.R., Martins, F.T., Villarreal, W., Machado, R.P., Doriguetto, A.C., Soares, M.B. and Bezerra, D.P., 2019. A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells. Redox biology, 20, pp.182-194. (Web Link)

[3] Jennings, S., Ng, H.P. and Wang, G., 2019. Establishment of a ΔF508-CF promyelocytic cell line for cystic fibrosis research and drug screening. Journal of Cystic Fibrosis, 18(1), pp.44-53. (Web Link)

 [4] Basophil-lineage commitment in acute promyelocytic leukemia predicts for severe bleeding after starting therapy

Sergio Matarraz, Pilar Leoz, […]Alberto Orfao

Modern Pathologyvolume 31, pages1318–1331 (2018) (Web Link)

[5] R. Samarakoon, S., Shanmuganathan, C., K. Ediriweera, M., Piyathilaka, P., H. Tennekoon, K. and Thabrew, I. (2016) “Screening of Fifteen Mangrove Plants Found in Sri Lanka for in-vitro Cytotoxic Properties on Breast (MCF-7) and Hepatocellular Carcinoma (HepG2) Cells”, European Journal of Medicinal Plants, 14(4), pp. 1-11. doi: 10.9734/EJMP/2016/26107. (Web Link)

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