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UID:952@biology.technion.ac.il

DTSTART;TZID=Asia/Jerusalem:20210427T130000

DTEND;TZID=Asia/Jerusalem:20210427T140000

DTSTAMP:20210802T125904Z

URL:https://biology.technion.ac.il/en/seminars/phd-graduate-seminar-may-le
 vin-2/

SUMMARY:PHD GRADUATE SEMINAR-May Levin [No Categories]
DESCRIPTION:Location:   \n Affiliation: \n Host:\n Mechanisms of chemoresis
 tance in relapsed AMLpatients: towards efficacious precision medicineAcute
 myeloid leukemia (AML) remains a devastating disease with a 5-year surviva
 lrate of less than 30%. AML treatment has undergone significant advances i
 nrecent years\, incorporating novel targeted therapies along with improvem
 ents inallogeneic bone marrow transplantation techniques. However\, the st
 andard ofcare remains cytarabine and anthracyclines\, and the primary hind
 rance towardscurative treatment is the frequent emergence of anticancer dr
 ug resistance. Herein\, we characterizedchemoresistance mechanisms in huma
 n leukemia cell lines in vitro and inspecimens derived from individual AML
  patients ex vivo. We further explored potential pre-clinical treatment st
 rategies tosurmount chemoresistanceas well as attempted to implement these
  findings towards efficacious personalized medicine.Todecipher the mechani
 sms underlying cytarabine resistance we establishedcytarabine-resistant su
 blines derived from human leukemia cells andcharacterized the expression o
 f cytarabine transport and metabolism genes usingreal-time PCR and Western
  blot analyses. These analyses were followed by growthinhibition assays an
 d isobologram analysis determining the sublines’sensitivity to the clini
 cally approved drugs hydroxyurea (HU) andazidothymidine (AZT)\, compared t
 o their parental cells.Cytarabine-resistant sublines displayed marked hype
 rsensitivityto HU and AZT compared to parental cells. The HU and AZT combi
 nation exhibiteda synergistic growth inhibitory effect on leukemia cells a
 nd AML patient specimens\,which was intensified upon acquisition of cytara
 bine resistance. These findingsestablish HU and AZT as a promising combina
 tion for the potential futuretreatment of relapsed and refractory AML.Towa
 rdsthe translation of these findings to the clinical setting\, we explored
  twocases of relapsed AML patients. We determined the expression levels of
  specificgenes mediating drug transport and metabolism\, nucleotide biosyn
 thesis\, andapoptosis\, to decipher the molecular mechanisms underlying in
 trinsic and/oracquired chemoresistance modalities in individual relapsed p
 atients. Thisanalysis revealed pre-existing differences in gene expression
  levels betweenthese relapsed patients and patients with lasting remission
 s following the sametreatment\, as well as drug-induced alterations at dif
 ferent relapse stagescompared to diagnosis.Ourfindings highlight the burni
 ng need for standardized evaluation of key drugtransport and metabolism ge
 nes as an integral component of routine AMLmanagement\, thereby allowing f
 or the tailoring of treatment regimens forindividual patients. This approa
 ch could facilitate the design of efficaciouspersonalized treatment regime
 ns\, thereby reducing relapse rates of a notorious therapyrefractory disea
 se. 

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