Novel pro-survival mechanisms of PIM2 in multiple myeloma

PIM2 在多发性骨髓瘤中的新的促生存机制

基本信息

  • 批准号:
    10668651
  • 负责人:
  • 金额:
    $ 59.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-04-15 至 2028-03-31
  • 项目状态:
    未结题

项目摘要

Multiple myeloma (MM) comprises 20% of all hematologic malignancies, second only to non-Hodgkin’s lymphoma, with 34,470 new cases and 12,640 deaths expected in 2022. Despite new therapeutics, MM remains incurable for almost all patients. The primary cause of treatment failure is upregulation of pro-survival mechanisms and progressively greater therapy resistance - thus defining these pro-survival responses will identify key therapeutic targets. The PIM family of serine/threonine kinases (PIM1, PIM2 and PIM3) have been shown to be oncogenic and overexpressed in a wide range of solid and hematological malignancies, with the highest level of PIM2 overexpression seen with MM disease progression. PIM kinases are constitutively active, and because the mRNA and protein have short half-lives their biological activity is dictated by regulation of their expression. Importantly, it is currently assumed that biological effects of PIM kinases are entirely due to their kinase activity. Bringing this assumption into question, we recently reported that the first-in-class PIM2-selective non-ATP-competitive inhibitor JP11646 (JP) caused significantly greater suppression of MM proliferation and viability compared to ATP-competitive PIM kinase inhibitors that equivalently inhibited PIM2 kinase activity. We found that JP’s increased efficacy was not due to superior inhibition of kinase activity, but rather to an unexpected downregulation of PIM2 gene and protein expression that did not occur with the ATP-competitive PIM2 kinase inhibitors. These observations led to our central hypothesis that PIM2 has critical but previously unrecognized kinase-independent (Ki) pro-survival function in MM – including maintaining high constitutive expression of the PIM2 gene. Preliminary studies have found that kinase-dead PIM2 mutants retain significant pro-survival activity. Mechanistically, we found that PIM2 stably interacts with the oncogene cMYC in MM cells and increases cMYC binding to several gene promoters - including PIM2 itself. Moreover, a cMYC inhibitor downregulated PIM2 expression, suggesting a novel auto-regulatory loop where PIM2 stabilizes cMYC binding and trans-activation of the PIM2 promoter – JP, but not ATP-competitive PIM kinase inhibitors, disrupts this loop. Additionally, we found that SLC25A11 and UCP2 – two genes coding mitochondrial metabolite transporters – are regulated by PIM2-cMYC axis in MM. Consistent with this, JP treatment or PIM2 knockdown selectively disrupted oxidative mitochondrial respiration, which we show is dependent on fatty acid oxidation (FAO). We propose to test a novel model of SLC25A11 and UCP2 overexpression reprogramming MM metabolism to favor FAO and promoting MM survival. Since JP has similar effects in acute myeloid leukemia and in solid tumors, PIM2 Ki function in MM may also occur to other cMYC-driven cancers. As such, inhibition of PIM2 Ki function may be a broadly applicable approach to target oncogenic cMYC activity. The Specific Aims proposed are: 1). To determine the kinase- independent mechanisms by which PIM2 supports MM survival, 2). To elucidate PIM2 auto-regulation in MM cells, and 3).To establish how PIM2 regulates MM metabolism independent of its kinase activity. 1
多发性骨髓瘤(MM)占所有血液恶性肿瘤的20%,仅次于非霍奇金淋巴瘤

项目成果

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KELVIN P. LEE其他文献

KELVIN P. LEE的其他文献

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{{ truncateString('KELVIN P. LEE', 18)}}的其他基金

Multidisciplinary Approaches to Tumor Immunology
肿瘤免疫学的多学科方法
  • 批准号:
    9769624
  • 财政年份:
    2019
  • 资助金额:
    $ 59.66万
  • 项目类别:
Durable humoral immunity regulated by intrinsic CD28 function in plasma cells
浆细胞内在 CD28 功能调节持久体液免疫
  • 批准号:
    8892983
  • 财政年份:
    2013
  • 资助金额:
    $ 59.66万
  • 项目类别:
Durable humoral immunity regulated by intrinsic CD28 function in plasma cells
浆细胞内在 CD28 功能调节持久体液免疫
  • 批准号:
    9115028
  • 财政年份:
    2013
  • 资助金额:
    $ 59.66万
  • 项目类别:
Durable humoral immunity regulated by intrinsic CD28 function in plasma cells
浆细胞内在 CD28 功能调节持久体液免疫
  • 批准号:
    8439086
  • 财政年份:
    2013
  • 资助金额:
    $ 59.66万
  • 项目类别:
Extramural Research Facility Construction Projects. Ros*
校外研究设施建设项目。
  • 批准号:
    7000560
  • 财政年份:
    2009
  • 资助金额:
    $ 59.66万
  • 项目类别:
Program Leaders
项目负责人
  • 批准号:
    7714406
  • 财政年份:
    2008
  • 资助金额:
    $ 59.66万
  • 项目类别:
CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival
CD28 介导的多发性骨髓瘤细胞增殖和存活的调节
  • 批准号:
    9260690
  • 财政年份:
    2007
  • 资助金额:
    $ 59.66万
  • 项目类别:
CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival
CD28 介导的多发性骨髓瘤细胞增殖和存活的调节
  • 批准号:
    8133375
  • 财政年份:
    2007
  • 资助金额:
    $ 59.66万
  • 项目类别:
CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival
CD28 介导的多发性骨髓瘤细胞增殖和存活的调节
  • 批准号:
    8692668
  • 财政年份:
    2007
  • 资助金额:
    $ 59.66万
  • 项目类别:
CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival
CD28 介导的多发性骨髓瘤细胞增殖和存活的调节
  • 批准号:
    7213526
  • 财政年份:
    2007
  • 资助金额:
    $ 59.66万
  • 项目类别:

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