Jurnal Internasional Kehilangan HAP1 memberikan resistensi l-asparaginase di ALL dengan menurunkan regulasi jalur calpain-1-Bid-caspase-3/12

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Jurnal Internasional Kehilangan HAP1 memberikan resistensi l-asparaginase di ALL dengan menurunkan regulasi jalur calpain-1-Bid-caspase-3/12

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Key Points

  • HAP1 loss in ALL prevents l -ASNase-evoked ER Ca 2+ releases and inhibits external Ca 2+ entries, reducing [Ca 2+ ] i [increased] and apoptotic cell death.

  • HAP1 was an ALL biomarker novel for l -ASNase resistance and can be used to define high-risk patients and design L-ASNase resistance therapy.

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Abstract

l -Asparaginase (1945914] l [1945915] -ASNase) is a strategic component of the treatment protocol for acute lymphoblastic leukemia (ALL). This causes a deficit of asparagine, which results in inhibition of protein synthesis and subsequent leukemia cell death and ALL remission. However, patients often relapse due to the development of resistance, but the mechanism underlying SEM cell resistance for lparaginase remains unknown. Through unbiased screening of genome RNA interference, we identified hunting of related proteins 1 (1945,905] HAP1 19459036) as ALL biomarkers for 1945-1915 resistance to parparaginase. Knocking down HAP1 induces l -paraginase resistance. HAP1 interacts with intracellular hunting and Ca channels, inositol 1,4,5-triphosphate receptors to form ternary complexes that mediate the endoplasmic reticulum (ER) Ca 2+ released after stimulation with inositol 1,4,5-triphosphate 3 . The loss of HAP1 prevented the formation of ternary complexes and hence l -asparaginase-mediated ER Ca 2+ was released. HAP1 losses also prevented external Ca [2] from entering, blocking excessive increases in [Ca 2+ i and reducing Ca activation 2 + -dependent calpain-1, Bid, and caspase-3 and caspase-12, cause reduced numbers of apoptotic cells. This finding suggests that HAP1 loss prevented apoptosis induced by paraphaginase through downregulation of Ca apoptotic intermediate calpain-1-Bid-caspase-3/12. Treatment with BAPTA-AM [12-bis(2-aminophenoxy)ethane- N, N, N ′, N N ′ – tetrakis tetraic acid (acetoxymethyl ester)] reverses [19459014[l][19451515-paraginaseeffectofapoptosisincontrolcellssupportingtherelationshipbetween[1945915] -asparaginase-induced [Ca 2+ ] i increased and apoptotic cell death . Consistent with these findings, ALL leukemic cells in patients with lower HAP1 levels showed resistance to 1945-paragagase, indicating the clinical relevance of the loss of HAP1 in the development of resistance to paraginase, and pointing to HAP1 as functional -paraginase resistance biomarkers that can be used for effective treatment designs -paraginase-resistant ALL.

  • Submitted December 5 2018. [19659012] Received February 26, 2019.

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