RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia

doi:10.1172/JCI141566

. 2021 Mar 15;131(6):e141566.

doi: 10.1172/JCI141566.

RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia

Filip Matthijssens^{1

2}, Nitesh D Sharma^{3

4}, Monique Nysus^{3

4}, Christian K Nickl^{3

4}, Huining Kang^{4

5}, Dominique R Perez^{4

6}, Beatrice Lintermans^{1

2}, Wouter Van Loocke^{1

2}, Juliette Roels^{1

2}, Sofie Peirs^{1

2}, Lisa Demoen^{1

2}, Tim Pieters^{1

2}, Lindy Reunes^{1

2}, Tim Lammens^{2

7}, Barbara De Moerloose^{2

7}, Filip Van Nieuwerburgh⁸, Dieter L Deforce⁸, Laurence C Cheung^{9

10}, Rishi S Kotecha^{9

10}, Martijn Dp Risseeuw^{2

11}, Serge Van Calenbergh^{2

11}, Takeshi Takarada¹², Yukio Yoneda¹³, Frederik W van Delft¹⁴, Richard B Lock¹⁵, Seth D Merkley⁵, Alexandre Chigaev^{4

6}, Larry A Sklar^{4

6}, Charles G Mullighan¹⁶, Mignon L Loh¹⁷, Stuart S Winter¹⁸, Stephen P Hunger¹⁹, Steven Goossens^{1

2

20}, Eliseo F Castillo⁵, Wojciech Ornatowski²¹, Pieter Van Vlierberghe^{1

2}, Ksenia Matlawska-Wasowska^{3

4}

Affiliations

¹ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
² Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
³ Department of Pediatrics, Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
⁴ Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.
⁵ Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
⁶ University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, USA.
⁷ Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
⁸ Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium.
⁹ Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
¹⁰ School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Western Australia, Australia.
¹¹ Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium.
¹² Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
¹³ Department of Pharmacology, Osaka University Graduate School of Dentistry, Suita, Japan.
¹⁴ Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom.
¹⁵ Children's Cancer Institute, School of Women's and Children's Health, Lowy Cancer Centre, University of New South Wales, Sydney, New South Wales, Australia.
¹⁶ Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
¹⁷ Department of Pediatrics, Benioff Children's Hospital, UCSF, San Francisco, California, USA.
¹⁸ Cancer and Blood Disorders Program, Children's Minnesota, Minneapolis, Minnesota, USA.
¹⁹ Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁰ Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
²¹ Department of Medicine, University of Arizona, Tucson, Arizona, USA.

PMID: 33555272
PMCID: PMC7954605
DOI: 10.1172/JCI141566

RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia

Filip Matthijssens et al. J Clin Invest. 2021.

. 2021 Mar 15;131(6):e141566.

doi: 10.1172/JCI141566.

Authors

Affiliations

¹ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
² Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
³ Department of Pediatrics, Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
⁴ Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA.
⁵ Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
⁶ University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, USA.
⁷ Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
⁸ Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium.
⁹ Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
¹⁰ School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Western Australia, Australia.
¹¹ Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium.
¹² Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
¹³ Department of Pharmacology, Osaka University Graduate School of Dentistry, Suita, Japan.
¹⁴ Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom.
¹⁵ Children's Cancer Institute, School of Women's and Children's Health, Lowy Cancer Centre, University of New South Wales, Sydney, New South Wales, Australia.
¹⁶ Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
¹⁷ Department of Pediatrics, Benioff Children's Hospital, UCSF, San Francisco, California, USA.
¹⁸ Cancer and Blood Disorders Program, Children's Minnesota, Minneapolis, Minnesota, USA.
¹⁹ Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁰ Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
²¹ Department of Medicine, University of Arizona, Tucson, Arizona, USA.

PMID: 33555272
PMCID: PMC7954605
DOI: 10.1172/JCI141566

Abstract

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show that Runt-related transcription factor 2 (RUNX2) was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We report direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion, and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrate that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its cofactor CBFβ. In conclusion, we show that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumor metabolism and leukemic cell migration.

Trial registration: ClinicalTrials.gov NCT01185886.

Keywords: Cell migration/adhesion; Leukemias; Molecular biology; Oncology.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

**Figure 1. *RUNX2* is upregulated in T-ALL harboring *KMT2A*-R and/or immature/ETP phenotype.**
(A) *RUNX2* expression across distinct molecular/genetic subtypes of T-ALL identified in a cohort of 242 pediatric and young adult T-ALL patients (8). (B) *RUNX2* mRNA levels in *HOXA*-deregulated T-ALL with chromosomal rearrangements involving the *KMT2A* gene (KMT2A-R, n = 11; other HOXA, n = 21) (8). (C) *RUNX2* expression in 189 T-ALL samples classified based on ETP (n = 19), near-ETP (n = 24), and non-ETP (n = 146) phenotype by flow cytometry (8). (D and E) *RUNX2* mRNA and protein levels in T-ALL cell lines (n = 9). (F) *RUNX2* mRNA expression in primary T-ALL samples depending on maturation arrest (n = 11) according to European Group for the Immunological Characterization of Acute Leukemias (EGIL) classification (103). (G) qRT-PCR analyses of *RUNX2* mRNA in primary T-ALL samples with or without *KMT2A*-R (*KMT2A*-R, n = 12; others, n = 13). Data are shown as mean ± SD, using 3 independent experiments. (H) Immunoblotting for RUNX2 protein levels in primary T-ALL samples (n = 9). Red font indicates *KMT2A*-R samples. (I) RUNX2 protein expression in PDX samples (n = 14) by flow cytometry. (A and C) Kruskal-Wallis with Dunn’s multiple comparison test; (B) unpaired Mann-Whitney U test. *P < 0.05; **P < 0.005; ***P < 0.0005; ****P < 0.0001.

**Figure 2. *RUNX2* is highly expressed in ETPs, but has no major impact on phenotypic markers of normal hematopoiesis or T cell development.**
*RUNX2* expression in human (A) and mouse (B) T cell subsets. (C) qRT-PCR for *Runx2* expression in cKit-enriched and cKit-negative mouse thymocytes. Rel., relative. (D and E) Peripheral blood cell counts measured in *Runx2^fl/flVaviCre^+/+* (Ctrl), *Runx2^fl/+VaviCre^tg/+* (Hez), and *Runx2^fl/flVaviCre^tg/+* (KO) mice (7–10 weeks). (F) Total cell number extracted from thymuses. (G–J) Percentages of T cell subsets measured by flow cytometry. (G) DP, double-negative T cells, (H) DN, double-positive T cells, (I) CD4 single-positive T cells, (J) CD8 single-positive T cells. (C) Paired 2-tailed t test; (D–J) 1-way ANOVA with Tukey’s multiple comparison test. ***P < 0.0005.

**Figure 3. RUNX2 regulates T-ALL survival.**
(A) Cell growth of LOUCY and KARPAS-45 cells transduced with *RUNX2* shRNAs (shRUNX2 B, shRUNX2 C) and scrambled control (shNC). Data are shown as mean ± SD for 1 of 3 independent experiments performed in triplicate. (B) Flow cytometry cell-cycle analysis using propidium iodide staining (48 hours). (C) Apoptotic cell death in T-ALL cells stained with annexin V/7-AAD (96 hours). (B and C) Data are representative of 1 of 3 independent experiments. (D) Human LOUCY and KARPAS-45 cells, murine MOHITO cells expressing control plasmid (CON), *KMT2A-R* (*KMT2A-MLLT1*, *KMT2A-MLLT4*), and primary T-ALL cells (PASSPP, 18-169) were transduced with *RUNX2* shRNAs and scrambled control. Western blot analysis of the indicated proteins. (E) RUNX2 and H3K27ac ChIP-Seq at the *CTNNB1* (β-catenin) and *BIRC5* (survivin) loci in KARPAS-45. Forced expression of (F) active β-catenin and (G) survivin in LOUCY with or without shRNA-mediated RUNX2 depletion. (H and I) Annexin V/7-ADD staining in LOUCY (96 hours). Data are shown as mean ± SD for 3 independent experiments. AnV, annexin V. (J) Kaplan-Meier survival curve analyses of NSG mice (n = 10/group) transplanted with 10⁶ LOUCY cells expressing shRUNX2 B, shRUNX2 C, or scrambled control (median log-rank Mantel-Cox test). (K) Flow cytometric quantification of human CD45⁺ cells in mice (n = 4/group) euthanized 41 days after inoculation with 10⁶ transduced LOUCY cells. (L) The levels of GFP⁺ cells were determined in blood (day 30), BM, and spleen (day 100) in animals injected with PDX samples harboring *KMT2A-MLLT-1*. (A) Repeated measure ANOVA with Tukey’s multiple comparisons test; (H, I, K, and L) 1-way ANOVA with Tukey’s multiple comparison test. ***P < 0.0005; ****P < 0.0001. (D, F, and G) Representative blots from at least 2 separate experiments.

**Figure 4. RUNX2 genome-wide binding profiles reveal a regulatory feedback loop with KMT2A fusion proteins.**
(A and B) Most highly enriched binding motifs according to HOMER upon RUNX2 ChIP-Seq in KARPAS-45 (*KMT2A*-R) and PER-117 (ETP). (C and D) Distribution of RUNX2 binding over different genomic regions in KARPAS-45 and PER-117. (E) MA plot showing differentially regulated genes (*P_Adj* < 0.05) in KARPAS-45, 72 hours after shRNA-mediated RUNX2 silencing vs. control in 5 biological replicates. (F–H) Top 10 enrichments of RUNX2-binding peaks based on functional annotation provided by GREAT (3.0.0). (I) RUNX2 and H3K27ac binding profile on the *KMT2A* gene region in KARPAS-45. (J) ChiP-qPCR on KARPAS-45 cells and 2 *KMT2A*-R primary T-ALL patient samples. Enrichment of RUNX2 on *KMT2A* promoter (left); enrichment of N-terminus of KMT2A (KMT2A^N) on *RUNX2* promoter (right). (K) Luciferase reporter assay for *KMT2A* on HEK293 cells transduced with *RUNX2* shRNA. The RUNX2 binding site is indicated as X (–359 to –368 bp upstream of *KMT2A* coding starting site). (L) Silencing of *RUNX2* leads to decreased levels of KMT2A^N in primary T-ALL samples. (M) *Runx2* expression in *KMT2A-MLLT1* transformed cells compared with lineage-depleted mouse progenitor cells. (N) Gradually increased expression of *Runx2* measured by qRT-PCR during *KMT2A-MLLT1* driven transformation over different replatings. (J) Unpaired 2-tailed t test with Holm-Šidák correction for multiple comparisons; (M) unpaired 2-tailed t test. *P < 0.05; ***P < 0.0005; ****P < 0.0001.

**Figure 5. *RUNX2* upregulation promotes T-ALL cell migration and leukemia progression.**
(A) Growth of CCRF-CEM and PF382 cells transduced with *RUNX2*-expressing (RUNX2 OE) or negative control (NC) plasmids. Data are shown as mean ± SD, 1 of 3 independent experiments performed in triplicate, repeated measure ANOVA with Tukey’s multiple comparisons test. (B) CXCR4 levels; representative histograms (left); median fluorescent intensity (MFI) ± SD, 3 independent experiments (right). Leukemic cell migration (6 hours) through (C) 3 μm porous membrane or (D) HUVEC monolayer ± CXCL12 (50 ng/μl). Data are shown as mean ± SEM, 3 separate experiments performed in duplicate. Two-way ANOVA with Tukey’s multiple comparison correction. (E) RUNX2 and H3K27ac binding at the *CXCR4* locus in KARPAS-45. (F) CCRF-CEM and PF382 transduced with RUNX2 OE or negative control; MOHITO cells expressing *KMT2A*-R (*KMT2A-MLLT1*, *KMT2A-MLLT4*) or negative control and primary T-ALL cells (PASSPP, 18-169) transduced with shRUNX2 B, shRUNX2 C, and scrambled control. Immunoblotting with indicated antibodies (n = 2). (G) Adhesion to fibronectin (2 hours). Data are shown as mean ± SD, 3 independent experiments performed in duplicate. (H) VLA-4 levels; representative histograms (left); MFI ± SD, 3 separate experiments (right). (I) Kaplan-Meier plot of NSG mice (n = 10/group) injected i.v. with 10⁶ PF382 cells (log-rank test). (J) Human CD45⁺ cells (day 34) and (K) bioluminescence imaging (NSG mice, n = 7/group) after interfemoral implantation of PF382 cells (3 × 10⁵). (L) BM homing of leukemic cells (24 hours); NSG mice (n = 5/group) received i.v. PF382 RUNX2 OE and negative control cells (10⁷; noncompetitive) or the mixture of fluorescently labeled PF382 RUNX2 OE (DsRed) and negative control (AmCyan) cells (1:1; 10⁷; competitive). Unpaired and paired 2-tailed t tests, respectively. (M) Human cytokines in blood serum of NSG mice inoculated with 10⁶ PF382 cells (day 28). (B, G, H, J, and M) Unpaired t test with Holm-Šidák multiple comparisons correction. **P < 0.005; ***P < 0.0005; ****P < 0.0001.

**Figure 6. RUNX2 potentiates glycolytic and oxidative metabolism in T-ALL cells.**
(A) CCRF-CEM and PF382 cells were transduced with *RUNX2* expressing (RUNX2 OE) and negative control plasmids. ECAR in glucose stress assay tested on the Seahorse XF24 Bioanalyzer. (B) Representative histograms for GLUT1 levels (top); MFI ± SD, 3 separate experiments (bottom). (C) Migration of T-ALL cells pretreated with glucose inhibitor (2DG, 1 mM; 16 hours) ± CXCL12 (50 ng/μl; 6 hours, 3 μm porous membrane). Data are represented as mean ± SD, 3 independent experiments performed in duplicate. (D) ECAR quantification and (E) GLUT1 levels in MOHITO-negative control cells, MOHITO-expressing *KMT2A-R* (*KMT2A-MLLT4*, *KMT2A-MLLT1*) and transduced with *RUNX2* shRNAs (shRUNX2 B, shRUNX2 C) or scrambled control. Representative histograms for GLUT1 expression (left); MFI ± SD, 3 independent experiments (right). OCR upon RUNX2 forced expression in (F) CCRF-CEM and (G) PF382 cells analyzed using Mito Stress assay on the Seahorse XF24 Bioanalyzer. (H) Plot representing OCR/ECAR ratios in RUNX2 OE vs. control cells. (I) OCR and (J) ratio of OCR/ECAR for MOHITO control cells and MOHITO cells with or without *KMT2A*-R followed by shRNA-mediated RUNX2 silencing. (K) RUNX2 and H3K27ac binding on the *LDHA*, *PGK1*, and *CHCHD2* gene regions in KARPAS-45. (L) Western blot analysis using indicated antibodies. Representative blots from at least 2 independent experiments. (A, D, and F–J) Data from 1 (mean ± SD) of 2 independent experiments performed in triplicate. (A, B, F, and G) Unpaired 2-tailed t test with Holm-Šidák correction for multiple comparisons; (C, D, and I) 2-way ANOVA with Tukey’s multiple comparison test; (E) 1-way ANOVA with Tukey’s multiple comparison test. *P < 0.05; **P < 0.005; ***P < 0.0005; ****P < 0.0001.

**Figure 7. RUNX2 positively regulates mitochondrial dynamics and biogenesis.**
(A) Mitochondria membrane potential (MitoTracker Red CMXRos) and (B) ROS levels (CellROS Deep Red) were tested by flow cytometry in CCRF-CEM and PF382 cells transduced with *RUNX2*-expressing (RUNX2 OE) and negative control plasmids. Representative histograms (left); MFI ± SD, 3 separate experiments (right). (C) Mitochondrial membrane potential and (D) ROS production in MOHITO negative control cells and MOHITO-expressing *KMT2A-R* (*KMT2A-MLLT4*, *KMT2A-MLLT1*) and transduced with *RUNX2* shRNAs (shRUNX2 B and shRUNX2 C) or scrambled control. Representative histograms and MFI ± SD, 3 independent experiments. (E and F) CCRF-CEM and PF382 cells with forced RUNX2 expression; MOHITO cells expressing control plasmid, *KMT2A-R* (*KMT2A-MLLT1*, *KMT2A-MLLT4*), and primary T-ALL cells (PASSPP, 18-169) were transduced with *RUNX2* shRNAs and scrambled control. Representative Western blot for the expression of specified proteins (n = 2). (G and H) Migration of CCRF-CEM and PF382 cells upon RUNX2 overexpression. Cells were pretreated with (G) a mitochondrial fission inhibitor, Mdivi-1 (1 μΜ, 16 hours), or (H) AMPK pathway inhibitor, dorsomorphin (1 μM, 16 hours), followed by migration through the 3 μm porous membrane in serum-free medium ± CXCL12 (50 ng/μl; 6 hours). Data are shown as mean ± SD, 3 separate experiments performed in duplicate. (A and B) Unpaired 2-tailed t test with Holm-Šidák correction for multiple comparisons; (C and D) 1-way ANOVA with Tukey’s multiple comparison test; (G and H) 2-way ANOVA with Tukey’s multiple comparison test. **P < 0.005; ***P < 0.0005; ****P < 0.0001.

**Figure 8. Immature T-ALL and *KMT2A*-rearranged leukemias are vulnerable to pharmacological targeting of the RUNX-CBFβ interaction.**
(A–D) Gene expression in *KMT2A-MLLT1* transformed mouse (*Runx2^fl/fl*; Cre Ert2^tg/+) BM progenitor cells. Full *Runx2* KO was achieved by treatment of transduced progenitor cells with 400 nM 4-hydroxytamoxifen for 24 hours prior to replating; vehicle-treated (EtOH) cells served as control (*Runx2* WT). RNA-Seq normalized gene counts for (A) *Runx1*, (B) *Hoxa10*, (C) *Hoxa11*, and (D) *Hoxb13*. (E) A panel of T-ALL cell lines showed reduced survival in vitro upon treatment with AI-10-104 (Cell-Titer Glo assay). (F) MA plot showing significantly (*P_Adj* < 0.05) upregulated (red) and downregulated (blue) genes in KARPAS-45 upon 24-hour treatment with 20 μM AI-10-104 compared with DMSO controls. Enriched gene set of mitochondrial inner membrane (MIM) genes represented in dark blue. Data based on 4 independent biological replicates. PDX samples from *KMT2A-MLLT1* (G) and *KMT2A-MLLT4* (H) patients showed reduced survival upon 24-hour treatment with AI-10-104. (A–D) Unpaired 2-tailed t test. *P < 0.05; **P < 0.005; ***P < 0.0005.

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References

1. Pui CH, et al. Acute lymphoblastic leukaemia. Lancet. 2008;371(9617):1030–1043. doi: 10.1016/S0140-6736(08)60457-2. - DOI - PubMed
1. Winter SS, et al. Improved survival for children and young adults with t-lineage acute lymphoblastic leukemia: results from the children’s oncology group AALL0434 methotrexate randomization. J Clin Oncol. 2018;36(29):2926–2934. doi: 10.1200/JCO.2018.77.7250. - DOI - PMC - PubMed
1. Armstrong SA, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002;30(1):41–47. doi: 10.1038/ng765. - DOI - PubMed
1. Ferrando AA, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1(1):75–87. doi: 10.1016/S1535-6108(02)00018-1. - DOI - PubMed
1. Homminga I, et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell. 2011;19(4):484–497. doi: 10.1016/j.ccr.2011.02.008. - DOI - PubMed

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[1] Pui CH, et al. Acute lymphoblastic leukaemia. Lancet. 2008;371(9617):1030–1043. doi: 10.1016/S0140-6736(08)60457-2. - DOI - PubMed

[2] Pui CH, et al. Acute lymphoblastic leukaemia. Lancet. 2008;371(9617):1030–1043. doi: 10.1016/S0140-6736(08)60457-2. - DOI - PubMed

[3] Winter SS, et al. Improved survival for children and young adults with t-lineage acute lymphoblastic leukemia: results from the children’s oncology group AALL0434 methotrexate randomization. J Clin Oncol. 2018;36(29):2926–2934. doi: 10.1200/JCO.2018.77.7250. - DOI - PMC - PubMed

[4] Winter SS, et al. Improved survival for children and young adults with t-lineage acute lymphoblastic leukemia: results from the children’s oncology group AALL0434 methotrexate randomization. J Clin Oncol. 2018;36(29):2926–2934. doi: 10.1200/JCO.2018.77.7250. - DOI - PMC - PubMed

[5] Armstrong SA, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002;30(1):41–47. doi: 10.1038/ng765. - DOI - PubMed

[6] Armstrong SA, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002;30(1):41–47. doi: 10.1038/ng765. - DOI - PubMed

[7] Ferrando AA, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1(1):75–87. doi: 10.1016/S1535-6108(02)00018-1. - DOI - PubMed

[8] Ferrando AA, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1(1):75–87. doi: 10.1016/S1535-6108(02)00018-1. - DOI - PubMed

[9] Homminga I, et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell. 2011;19(4):484–497. doi: 10.1016/j.ccr.2011.02.008. - DOI - PubMed

[10] Homminga I, et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell. 2011;19(4):484–497. doi: 10.1016/j.ccr.2011.02.008. - DOI - PubMed

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RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia

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RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia

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