Targeting Microenvironmental Signals in Myeloid Malignancies
靶向髓系恶性肿瘤中的微环境信号
基本信息
- 批准号:10344681
- 负责人:
- 金额:$ 39.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:Activities of Daily LivingAcute Myelocytic LeukemiaAddressAdhesivesAdultBlast PhaseBone MarrowCRISPR screenCell DeathCell LineCell surfaceCellsChronic Myeloid LeukemiaClustered Regularly Interspaced Short Palindromic RepeatsDataData SetDevelopmentDiseaseDisease ProgressionDisease modelEndothelial CellsEnvironmentEnzymesGenesGeneticGoalsGrowthHematopoiesisHematopoietic stem cellsHumanImpairmentIn VitroKnowledgeLeadLeukemic CellMLL-AF9Malignant NeoplasmsMediatingMissionMusMutationMyelogenousMyeloid LeukemiaMyeloproliferative diseaseNon-Essential Amino AcidOncogenesOsteoblastsPatientsPilot ProjectsPrognosisPublic HealthReceptor SignalingResistanceRoleSignal TransductionStromal CellsSurface AntigensSurvival RateTaurineTestingThe Cancer Genome AtlasUnited States National Institutes of HealthWorkXenograft Modelacute myeloid leukemia celladult stem cellbasebonecancer celldisabilitygenome-widein vivointerestknock-downleukemialeukemic stem cellleukemogenesismouse modelmyeloid leukemia cellnew therapeutic targetnovelosteogenicosteoprogenitor cellreconstitutionself-renewalsingle-cell RNA sequencingsmall hairpin RNAstemstem cell self renewalstem cellstaurine transportertherapy resistanttranscriptome sequencing
项目摘要
ABSTRACT
Interactions of stem cells with their surrounding microenvironment are known to be essential for both normal
development, and for sustaining self-renewing adult stem cells, such as the hematopoietic stem cells (HSCs).
Since cancers often hijack developmental signals for their progression, it is likely that niche-driven signals that
sustain HSCs also influence the growth of leukemias arising from mutations in HSCs and early hematopoietic
progenitors, such as acute myeloid leukemia (AML) and blast crisis chronic myeloid leukemia (bcCML). Despite
recent advances in treatment, ~75% of AML patients still succumb to the disease, highlighting the need to better
understand mechanisms of disease progression. While much work has focused on leukemia cell-intrinsic
regulators, the role of the microenvironment in disease establishment and propagation is poorly understood. Our
overall goal is to define the role of leukemia-niche interactions on myeloid leukemogenesis. In support of a
functional role of the niche in disease progression, our work has shown that adhesive interaction of AML with
endothelial cells is critical to maintain the therapy-resistant leukemia stem cells (LSCs). Since osteoprogenitors
expand in the leukemic bone marrow, it is possible that these osteoprogenitors also create a cancer-supporting
microenvironment. As an alternate to identifying niche-driven signals promoting leukemogenesis, we determined
cell surface antigens expressed on LSCs that can act as receptors for these signals using our recent in vivo
genome-wide CRISPR screen. The 140 cell surface genes identified by our screen included those known to
promote leukemia growth (e.g., Cd47, Cd157) and novel regulators of leukemia progression. To focus on signals
likely to be cancer-specific, we selected a subset of novel cell-surface regulators with 2-fold higher expression
in human bcCML LSCs compared to normal HSCs in our new RNA-seq dataset. Of these, the taurine transporter
SLC6A6 (TauT) is of particular interest since its high expression is associated with poor prognosis in AML
(TCGA). Using TauT-/- mice, we find that genetic loss of TauT significantly impairs leukemia growth in vivo as
compared to TauT+/+. Our key preliminary data show that enzymes for synthesis of the non-essential amino acid
taurine are upregulated with osteolineage differentiation of bone marrow stromal cells, and taurine is secreted in
the environment. Based on our pilot studies showing taurine synthesis by osteoprogenitors, a requirement for
LSC TauT expression for cancer growth, and expansion of osteoprogenitors in AML, we hypothesize that
osteoprogenitors sustain LSCs and support leukemia progression by secreting taurine. We will now test if TauT
expression is essential for disease progression in mouse models of disease, as well as for the propagation of
primary human leukemias. We will also determine if osteoprogenitors form a supportive microenvironment for
leukemia progression by secreting taurine. Collectively, these studies will establish the role of taurine from the
bone marrow osteolineage niche in myeloid leukemia progression. In the long term this work may lead to
development of new therapies targeting microenvironmental signals supporting cancer cells.
摘要
项目成果
期刊论文数量(0)
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Jeevisha Bajaj其他文献
Jeevisha Bajaj的其他文献
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{{ truncateString('Jeevisha Bajaj', 18)}}的其他基金
Targeting Microenvironmental Signals in Myeloid Malignancies
靶向髓系恶性肿瘤中的微环境信号
- 批准号:
10651619 - 财政年份:2022
- 资助金额:
$ 39.59万 - 项目类别:
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