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The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG

Haobin Ye, Mohammad Minhajuddin, Anna Krug, Shanshan Pei, Chih-Hsing Chou, Rachel Culp-Hill, Jessica Ponder, Erik De Bloois, Björn Schniedewind, Maria L. Amaya, Anagha Inguva, Brett M. Stevens, Daniel A. Pollyea, Uwe Christians, H. Leighton Grimes, Angelo D'Alessandro and Craig T. Jordan
Haobin Ye
1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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  • For correspondence: craig.jordan@cuanschutz.edu haobin.ye@cuanschutz.edu
Mohammad Minhajuddin
1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Anna Krug
1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Shanshan Pei
1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Chih-Hsing Chou
2Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, Ohio.
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Rachel Culp-Hill
3Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Jessica Ponder
1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Erik De Bloois
4Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Björn Schniedewind
4Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Maria L. Amaya
1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Anagha Inguva
1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Brett M. Stevens
1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Daniel A. Pollyea
1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Uwe Christians
4Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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H. Leighton Grimes
2Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, Ohio.
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Angelo D'Alessandro
1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
3Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Craig T. Jordan
1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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  • For correspondence: craig.jordan@cuanschutz.edu haobin.ye@cuanschutz.edu
DOI: 10.1158/2159-8290.CD-20-0318 Published February 2021
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    Figure 1.

    Liver is an extramedullary reservoir for LSCs. A and B, BM and liver leukemic burden (A) and LSC percentage (B) in leukemia mice at day 12 after leukemic transplantation (n = 4). C, Liver and bone were harvested at indicated time points post leukemic transplantation. Leukemic burden, LSC percentage, leukemia cell number, and LSC cell number were determined (per whole liver or per femur + tibia). Hematoxylin and eosin (H&E) staining of liver sections from leukemic mice are shown at the top. For 10X, scale bar represents 100 μm; for 20X, scale bar represents 50 μm. D, LSC frequency in BM and liver leukemia cells accessed by limiting dilution assays. E and F, BM and liver leukemic burden (E) and leukemia progenitor percentage (F) in FDN mice at day 24 after leukemic transplantation (n = 8). (continued on next page) G, Mice were injected with cells that contain ∼50% leukemia cells (GFP+/YFP+ cells; 20 million cells/mouse). BM and liver leukemia cell percentages were examined 16 hours after injection (n = 6). H and I, Leukemic mice were treated with chemotherapy consisting of 5-day treatment of Ara-C (100 mg/kg, i.p.) and 3-day treatment of doxorubicin (3 mg/kg, i.p., first 3 days). BM and liver leukemic burden, leukemia cell number, fold change of leukemia cell number (H), and LSC percentage (I) were examined after chemotherapy (n = 4). Error bars denote mean ± SD. *, P < 0.05; **, P < 0.005; ***, P < 0.0005; ****, P < 0.00005.

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    Figure 2.

    Liver-resident LSCs are distinct in gene signature and metabolism. A, Heat map showing transcriptome comparison between BM and liver LSCs (left). Enriched signaling pathways in liver LSCs are shown on the right. B, Leukemic mice were injected with BrdUrd (2 mg/kg, i.p.). Mice were sacrificed 90 minutes after injection and tissues were harvested to detect the incorporation of BrdUrd into LSCs (n = 5). C and D, Relative amount of different PUFA species in BM and liver lin− leukemia cells from the bcCML model (C; n = 4) and in BM and liver c-kit+/lin−leukemic progenitors from FDN models (D; n = 7). LA, linoleic acid; ETA, eicosatetraenoic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; DGLA, dihomo-γ-linolenic acid; DPA, docosapentaenoic acid. E, LSCs were isolated and cultured in vitro with the presence of different PUFA species (10 μmol/L for each PUFA). LSC cell numbers were determined after 2-day culturing. Error bars denote mean ± SD from triplicates. F, Leukemic mice were treated with sodium linoleate starting day 2 after leukemic transplantation (200 mg/kg, i.p.). Mice were sacrificed at day 12 after leukemic transplantation and tissues were harvested to determine BM and liver leukemic burden (n = 4). G, Lin− leukemia cells were treated either with indicated doses of LA for 45 minutes or with LA (20 μmol/L) for indicated time periods. Cells were harvested to determine ERK activation. H, Lin− leukemia cells were isolated from BM and liver and the expression of indicated proteins were examined by immunoblot. I, Leukemic mice were treated with the ERK inhibitor SCH772984 (50 mg/kg, i.p.) starting day 5 after leukemic transplantation. Mice were sacrificed at day 12 after leukemic transplantation and tissues were harvested to determine BM and liver leukemic burden (n = 4). Error bars denote mean ± SD. *, P < 0.05; **, P < 0.005.

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    Figure 3.

    LIPG regulates PUFA metabolism and protects LSCs from chemotherapy. A, GSEA showing enrichment of the glycerolipid metabolism pathway in liver LSCs. B, LIPG mRNA level in BM and liver LSCs. Error bars denote mean ± SD from triplicates. C, Plasma HDL and VLDL/LDL levels in normal and leukemic mice (n = 6–7). D, Cellular amount of different PUFA species in vector-expressing and LIPG-OE lin− leukemia cells (n = 4). E, Vector-expressing and LIPG-OE lin− leukemia cells were isolated and cultured with or without the presence of HDL (100 μg/mL) for 24 hours and cell number was determined. Error bars denote mean ± SD from triplicates. F, Vector-expressing and LIPG-OE lin− leukemia cells were treated with HDL (200 μg/mL) for 30 minutes, and cells were harvested to examine ERK activation. G, Vector-expressing and LIPG-OE lin− leukemia cells were isolated and cultured with or without the presence of HDL (100 μg/mL) or SCH772984 (1 μmol/L) for 24 hours and cell number was determined. Error bars denote mean ± SD from triplicates. H, Mice were transplanted with vector-expressing or LIPG-OE bulk leukemia cells (GFP+/YFP+ cells). One cohort of mice was treated with chemotherapy consisting of 5-day treatment of Ara-C (50 mg/kg, i.p.) and 3-day treatment of doxorubicin (1.5 mg/kg, i.p., first 3 days) starting day 8 after transplantation. The other cohort was untreated. Mice were sacrificed at day 13 after transplantation. Leukemic burden, leukemic cell number (per whole liver or per femur + tibia), and fold change in BM and liver were determined (n = 4–5). I, Viability of vector-expressing and LIPG-OE bulk leukemia cells after 24 hours of culturing. Error bars denote mean ± SD from triplicates. J, Survival of mice transplanted with LIPG-OE or vector-expressing leukemia cells (10,000 bulk leukemia cells/mouse) treated with or without chemotherapy (same regimen shown in H; n = 7). Error bars denote mean ± SD. *, P < 0.05; **, P < 0.005; ***, P < 0.0005; ****, P < 0.00005.

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    Figure 4.

    LIPG regulates expression of BCL2 and BCL-XL. A, Expression of antiapoptotic proteins in vector-expressing and LIPG-OE lin− leukemia cells. B, Schematic diagram for mouse treatment. C, BM leukemic burden in mice transplanted with vector-expressing or LIPG-OE bulk leukemia cells treated with vehicle or ABT-263 (50 mg/kg, p.o.; n = 5). D and E, Mice were transplanted with vector-expressing or LIPG-OE bulk leukemia cells and treated with chemotherapy consisting of 5-day treatment of Ara-C (50 mg/kg, i.p.) and 3-day treatment of doxorubicin (1.5 mg/kg, i.p., first 3 days) or ABT-chemotherapy consisting of chemotherapy and ABT-263 (n = 5). BM leukemic burden (D) and LSC percentage (E) were determined after therapy. F and G, Mice transplanted with parental bulk leukemia cells were treated with chemotherapy or ABT-chemotherapy starting day 8 after transplantation. Liver leukemia burden (F) and LSC percentage (G) were determined at day 13 after transplantation (n = 5). H, Mice were transplanted with parental bulk leukemia cells and treated with vehicle, ABT-263, chemotherapy alone, or ABT-chemotherapy. Survival of leukemic mice was monitored (n = 7). Error bars denote mean ± SD. *, P < 0.05; **, P < 0.005; ***, P < 0.0005; ****, P < 0.00005.

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    Figure 5.

    Endogenous LIPG is critical for the proliferation and chemoresistance of liver-resident leukemia cells. A and B, Mice were transplanted with control or LIPG KO bulk leukemia cells. One cohort of mice was treated with chemotherapy consisting of 5-day treatment of Ara-C (50 mg/kg, i.p.) and 3-day treatment of doxorubicin (1.5 mg/kg, i.p., first 3 days) starting day 8 after transplantation. The other cohort was untreated. Mice were sacrificed at day 13 after transplantation. Leukemic burden, leukemic cell number (per whole liver or per femur + tibia), and fold change (A) and LSC percentage (B) in BM and liver were determined (n = 4). C, Phosphorylation of ERK in control and LIPG KO lin− leukemia cells. D, LA level in control and LIPG KO lin− leukemia cells (n = 3). E, Survival of mice transplanted with control or LIPG KO leukemia cells (10,000 bulk leukemia cells/mouse) treated with or without chemotherapy (same regimen shown in A; n = 7). F, Expression of antiapoptotic proteins in control and LIPG KO lin− leukemia cells. G, mRNA levels of antiapoptotic proteins in LIPG-OE, LIPG KO, and control lin− leukemia cells. Error bars denote mean ± SD from triplicates. H, LIPG-OE, LIPG KO, and control lin− leukemia cells were treated with indicated doses of cycloheximide for indicated time periods. BCL-XL protein level was examined. Error bars denote mean ± SD.*, P < 0.05; **, P < 0.005; ***, P < 0.0005.

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    Figure 6.

    Leukemic infiltration induces liver damage and creates a chemoprotective microenvironment. A–D, AST (A), ALT (B), XO (C), and CDA (D) activities in sera from normal and leukemic mice (n = 4). E, Ara-C was preincubated with serum from normal or leukemic mice or H2O for 24 hours at 37°C. One group of bulk leukemia cells was treated with preincubated Ara-C; the other group was treated with Ara-C without preincubation and supplemented with equal amount of either normal or leukemic serum as the first group. Viability of leukemia cells was examined 24 hours after treatment. Error bars denote mean ± SD from triplicates. F, Relative serum xanthine and hypoxanthine levels in normal and leukemic mice (n = 4). G, Ara-C was incubated with normal or leukemic serum for 24 hours at 37°C (final concentration of cytarabine: 100 nmol/L). Ara-C and Ara-U concentration was determined by mass spectrometry after incubation (n = 6). H and I, Plasma activity of AST (H) and CDA (I) in portal vein (In) and hepatic vein (Out) from normal and leukemic mice (n = 5). J, Leukemic mice were treated with short-term chemotherapy [consisting of 2-day treatment of Ara-C (50 mg/kg, i.p.) and doxorubicin (1.5 mg/kg, i.p.)]. BM and liver leukemic burden, leukemic cell number (per whole liver or per femur + tibia), and leukemia cell number fold change were determined (n = 5). Error bars denote mean ± SD. *, P < 0.05; **, P < 0.005; ***, P < 0.0005; ****, P < 0.00005.

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    Figure 7.

    Human leukemia cells infiltrate liver and display similar phenotypes. A, Engraftment of human leukemia cells (hCD45+ cells) in BM and perfused liver in NSG mice transplanted with different patient samples (n = 4–6). B, Leukemic NSG mice were injected with BrdUrd (2 mg/kg, i.p.). Mice were sacrificed 180 minutes after injection, and tissues were harvested to detect the incorporation of BrdUrd into human leukemia cells (n = 3–5). C, Liver and BM human leukemia cells were isolated from leukemic NSG mice. PUFA levels were determined in these cells (n = 5–7). D, BM and liver human leukemic cells were isolated from leukemic NSG mice. Expression of indicated proteins was determined by immunoblot. E, Leukemic patient cells were treated with LA (20 μmol/L) for 45 minutes. Cells were harvested to determine ERK activation. F, Leukemic NSG mice were treated with LA starting day 5 after transplantation (200 mg/kg, i.p., every other day). Mice were taken down at day 30 after transplantation. BM and liver leukemic burden were examined (n = 5). (continued on next page) G, Leukemic NSG mice were treated with SCH772984 starting day 25 after transplantation (50 mg/kg, i.p., every other day). Mice were sacrificed at day 50 after transplantation. BM and liver leukemic burden were examined (n = 5). H, Leukemic NSG mice were treated with chemotherapy consisting of 3-day treatment of doxorubicin (1 mg/kg, i.p., first 3 days) and 5-day treatment of Ara-C (30 mg/kg, i.p.) starting day 35 after transplantation. After chemotherapy, mice were sacrificed to determine BM and liver leukemic burden, leukemic cell number (per whole liver or per femur + tibia), and fold change (n = 6). I, Expression of LIPG mRNA was determined in BM and liver leukemia cells isolated from leukemic NSG mice. Error bars denote mean ± SD from triplicates. J, Plasma HDL and VLDL/LDL levels in normal controls (n = 7) and patients with AML (n = 16). K, Expression of LIPG mRNA in surviving leukemia patient cells after 24- and 48-hour treatment of Ara-C (7.5 μmol/L) or doxorubicin (Doxo; 5 μmol/L). Error bars denote mean ± SD from triplicates. (continued on following page) L, Expression of BCL2 and BCL-XL proteins in surviving leukemia patient cells after 48-hour treatment with Ara-C (A; 7.5 μmol/L)or doxorubicin (D; 5 μmol/L). V represents vehicle. M, Leukemia patient cells were treated with either vehicle, ABT-263 (0.5 μmol/L), chemotherapeutic drugs (7.5 μmol/L Ara-C or 5 μmol/L doxorubicin), or chemotherapeutic drugs combined with ABT-263. Cell viability was examined 24 and 48 hours after treatment. N–Q, Plasma activities of ALT (N), AST (O), GGT (P), and CDA (Q) in normal controls (n = 7) and patients with AML (n = 16). R, Ara-C was preincubated with plasma from normal controls or patients with leukemia or H2O for 24 hours at 37°C. One group of human bcCML cells was treated with preincubated Ara-C; the other group was treated with Ara-C without preincubation and supplemented with equal amount of either normal or leukemic plasma as the first group. Viability was examined 24 hours after treatment. Error bars denote mean ± SD from triplicates. Error bars denote mean ± SD from triplicates. S, Working model for the protective function of the liver niche. Liver niche induces expression of LIPG, which enables leukemia cells to utilize HDL in the microenvironment and converts phospholipids in HDL to PUFAs. PUFA activates the ERK signaling pathway and promotes proliferation of leukemia cells. Additionally, hepatic infiltration of leukemia cells leads to liver damage and causes release of enzymes capable of degrading chemotherapy drugs, further protecting leukemia cells from chemotherapy. Error bars denote mean ± SD. *, P < 0.05; **, P < 0.005; ****, P < 0.00005.

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Cancer Discovery: 11 (2)
February 2021
Volume 11, Issue 2
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The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG
Haobin Ye, Mohammad Minhajuddin, Anna Krug, Shanshan Pei, Chih-Hsing Chou, Rachel Culp-Hill, Jessica Ponder, Erik De Bloois, Björn Schniedewind, Maria L. Amaya, Anagha Inguva, Brett M. Stevens, Daniel A. Pollyea, Uwe Christians, H. Leighton Grimes, Angelo D'Alessandro and Craig T. Jordan
Cancer Discov February 1 2021 (11) (2) 500-519; DOI: 10.1158/2159-8290.CD-20-0318

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The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG
Haobin Ye, Mohammad Minhajuddin, Anna Krug, Shanshan Pei, Chih-Hsing Chou, Rachel Culp-Hill, Jessica Ponder, Erik De Bloois, Björn Schniedewind, Maria L. Amaya, Anagha Inguva, Brett M. Stevens, Daniel A. Pollyea, Uwe Christians, H. Leighton Grimes, Angelo D'Alessandro and Craig T. Jordan
Cancer Discov February 1 2021 (11) (2) 500-519; DOI: 10.1158/2159-8290.CD-20-0318
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