Summary of Study ST002446

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001577. The data can be accessed directly via it's Project DOI: 10.21228/M8VD8T This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002446
Study TitleUntargeted metabolomics of miR-142 WT vs KO CML cells
Study SummaryMiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.
Institute
Translational Genomics Research Institute
Last NameMansfield
First NameKrystine
Address445 N 5th St, Phoenix, AZ, 85004, USA
Emailkgarcia@tgen.org
Phone602-343-8832
Submit Date2023-01-13
Num Groups2
Total Subjects18
Num Males9
Num Females9
Raw Data AvailableYes
Raw Data File Type(s)mzML
Analysis Type DetailLC-MS
Release Date2023-08-08
Release Version1
Krystine Mansfield Krystine Mansfield
https://dx.doi.org/10.21228/M8VD8T
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Factors:

Subject type: Cultured cells; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Genotype
SA244647Norm. Area: 088_0003_02E_R_A12xKOxFx04xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F209)KO
SA244648Norm. Area: 088_0003_02E_R_A11xKOxFx03xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F208)KO
SA244649Norm. Area: 088_0003_02E_R_A13xKOxFx05xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F210)KO
SA244650Norm. Area: 088_0003_02E_R_A14xKOxMx01xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F211)KO
SA244651Norm. Area: 088_0003_02E_R_A15xKOxMx02xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F212)KO
SA244652Norm. Area: 088_0003_02E_R_A10xKOxFx02xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F207)KO
SA244653Norm. Area: 088_0003_02B_R_A09xKOxFx01xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F9)KO
SA244654Norm. Area: 088_0003_02G_R_A15xKOxMx02conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F151)KO
SA244655Norm. Area: 088_0003_02G_R_A16xKOxMx03conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F152)KO
SA244656Norm. Area: 088_0003_02G_R_A17xKOxMx04conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F153)KO
SA244657Norm. Area: 088_0003_02G_R_A18xKOxMx05conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F154)KO
SA244658Norm. Area: 088_0003_02E_R_A16xKOxMx03xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F213)KO
SA244659Norm. Area: 088_0003_02E_R_A18xKOxMx05xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F215)KO
SA244660Norm. Area: 088_0003_02D_R_A15xKOxMx02xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F181)KO
SA244661Norm. Area: 088_0003_02D_R_A14xKOxMx01xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F180)KO
SA244662Norm. Area: 088_0003_02D_R_A16xKOxMx03xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F182)KO
SA244663Norm. Area: 088_0003_02D_R_A17xKOxMx04xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F183)KO
SA244664Norm. Area: 088_0003_02D_R_A18xKOxMx05xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F184)KO
SA244665Norm. Area: 088_0003_02D_R_A13xKOxFx05xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F179)KO
SA244666Norm. Area: 088_0003_02D_R_A12xKOxFx04xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F178)KO
SA244667Norm. Area: 088_0003_02G_R_A14xKOxMx01conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F150)KO
SA244668Norm. Area: 088_0003_02D_R_A09xKOxFx01xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F175)KO
SA244669Norm. Area: 088_0003_02D_R_A10xKOxFx02xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F176)KO
SA244670Norm. Area: 088_0003_02D_R_A11xKOxFx03xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F177)KO
SA244671Norm. Area: 088_0003_02E_R_A17xKOxMx04xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F214)KO
SA244672Norm. Area: 088_0003_02E_R_A09xKOxFx01xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F206)KO
SA244673Norm. Area: 088_0003_02B_R_A15xKOxMx02xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F15)KO
SA244674Norm. Area: 088_0003_02B_R_A16xKOxMx03xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F16)KO
SA244675Norm. Area: 088_0003_02B_R_A18xKOxMx05xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F18)KO
SA244676Norm. Area: 088_0003_02G_R_A09xKOxFx01conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F145)KO
SA244677Norm. Area: 088_0003_02B_R_A14xKOxMx01xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F14)KO
SA244678Norm. Area: 088_0003_02B_R_A13xKOxFx05xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F13)KO
SA244679Norm. Area: 088_0003_02B_R_A10xKOxFx02xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F10)KO
SA244680Norm. Area: 088_0003_02B_R_A11xKOxFx03xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F11)KO
SA244681Norm. Area: 088_0003_02B_R_A12xKOxFx04xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F12)KO
SA244682Norm. Area: 088_0003_02G_R_A10xKOxFx02conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F146)KO
SA244683Norm. Area: 088_0003_02B_R_A17xKOxMx04xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F17)KO
SA244684Norm. Area: 088_0003_02G_R_A13xKOxFx05conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F149)KO
SA244685Norm. Area: 088_0003_02G_R_A11xKOxFx03conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F147)KO
SA244686Norm. Area: 088_0003_02G_R_A12xKOxFx04conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F148)KO
SA244687Norm. Area: 088_0003_02D_R_A04xWTxFx04xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F170)WT
SA244688Norm. Area: 088_0003_02B_R_A02xWTxFx02xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F2)WT
SA244689Norm. Area: 088_0003_02D_R_A03xWTxFx03xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F169)WT
SA244690Norm. Area: 088_0003_02D_R_A01xWTxFx01xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F167)WT
SA244691Norm. Area: 088_0003_02B_R_A03xWTxFx03xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F3)WT
SA244692Norm. Area: 088_0003_02B_R_A01xWTxFx01xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F1)WT
SA244693Norm. Area: 088_0003_02D_R_A02xWTxFx02xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F168)WT
SA244694Norm. Area: 088_0003_02G_R_A01xWTxFx01conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F137)WT
SA244695Norm. Area: 088_0003_02D_R_A08xWTxMx04xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F174)WT
SA244696Norm. Area: 088_0003_02G_R_A03xWTxFx03conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F139)WT
SA244697Norm. Area: 088_0003_02D_R_A07xWTxMx03xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F173)WT
SA244698Norm. Area: 088_0003_02D_R_A06xWTxMx02xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F172)WT
SA244699Norm. Area: 088_0003_02G_R_A02xWTxFx02conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F138)WT
SA244700Norm. Area: 088_0003_02D_R_A05xWTxMx01xconcRPpos_21SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F171)WT
SA244701Norm. Area: 088_0003_02B_R_A04xWTxFx04xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F4)WT
SA244702Norm. Area: 088_0003_02G_R_A06xWTxMx02conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F142)WT
SA244703Norm. Area: 088_0003_02E_R_A04xWTxFx04xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F201)WT
SA244704Norm. Area: 088_0003_02B_R_A07xWTxMx03xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F7)WT
SA244705Norm. Area: 088_0003_02B_R_A06xWTxMx02xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F6)WT
SA244706Norm. Area: 088_0003_02E_R_A03xWTxFx03xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F200)WT
SA244707Norm. Area: 088_0003_02E_R_A02xWTxFx02xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F199)WT
SA244708Norm. Area: 088_0003_02B_R_A08xWTxMx04xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F8)WT
SA244709Norm. Area: 088_0003_02E_R_A01xWTxFx01xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F198)WT
SA244710Norm. Area: 088_0003_02B_R_A05xWTxMx01xHILICpos_09SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F5)WT
SA244711Norm. Area: 088_0003_02G_R_A08xWTxMx04conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F144)WT
SA244712Norm. Area: 088_0003_02E_R_A08xWTxMx04xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F205)WT
SA244713Norm. Area: 088_0003_02G_R_A07xWTxMx03conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F143)WT
SA244714Norm. Area: 088_0003_02E_R_A07xWTxMx03xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F204)WT
SA244715Norm. Area: 088_0003_02E_R_A06xWTxMx02xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F203)WT
SA244716Norm. Area: 088_0003_02G_R_A04xWTxFx04conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F140)WT
SA244717Norm. Area: 088_0003_02E_R_A05xWTxMx01xconcRPneg_28SEP21_CEL_MOU_LUM_0000_04AC_15MIN_KP_KP_01.raw (F202)WT
SA244718Norm. Area: 088_0003_02G_R_A05xWTxMx01conxHILICneg_29SEP21_CEL_MOU_LUM_0000_04AB_15MIN_KP_KP_01.raw (F141)WT
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