American Association for Cancer Research
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Supplementary Figures S1-S12 and Supplementary Tables S1 and S3 from Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL

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journal contribution
posted on 2023-03-31, 02:07 authored by Alberto Martín-Lorenzo, Franziska Auer, Lai N. Chan, Idoia García-Ramírez, Inés González-Herrero, Guillermo Rodríguez-Hernández, Christoph Bartenhagen, Martin Dugas, Michael Gombert, Sebastian Ginzel, Oscar Blanco, Alberto Orfao, Diego Alonso-López, Javier De Las Rivas, Maria B. García-Cenador, Francisco J. García-Criado, Markus Müschen, Isidro Sánchez-García, Arndt Borkhardt, Carolina Vicente-Dueñas, Julia Hauer

Supplementary Figure 1: Mouse generation and GSEA enrichment analysis of Sca1-BCR-ABLp190 mice. Supplementary Figure 2: Time course of the percentage of B220+ cells in PB of Sca1-BCR-ABLp190 and Sca1-BCR-ABLp190+Pax5+/- mice. Supplementary figure 3: pB-ALL is transplantable to secondary recipients. Supplementary figure 4: Sca1-BCR-ABLp190+Pax5+/- mice housed in SPF develop similar pB-ALL than Sca1-BCR-ABLp190+Pax5+/- mice housed in CF Supplementary Figure 5: transcriptome analysis of Sca1-BCR-ABLp190+Pax5+/- mice. Supplementary Figure 6: Mouse tumor exome sequencing data identified recurrent Pax5 mutations. Supplementary Figure 7: Polyclonal VDJ recombination events in pre-leukemic B220-positive cells from the BM of Sca1-BCR-ABLp190+Pax5+/- mice Supplementary Figure 8: Altered pathways in leukemic Sca1-BCR-ABLp190+Pax5+/-. Supplementary Figure 9: Quantitative differences of mRNA levels of glycolytic related genes between leukemic Sca1-BCR-ABLp190+Pax5+/-, Sca1-BCR-ABLp190 and wild-type B cells. Supplementary Figure 10: QRT-PCR validation of microarray data. Supplementary Figure 11: Metabolic signature in human pB-ALLs. Supplementary Figure 12: Analysis of ChIP-seq data revealed novel targets of PAX5 in human B lymphocytes. Supplementary Table 1: Percentage and total numbers of hematopoietic progenitor compartments in young Sca1-BCR-ABLp190 and wild type mice. Supplementary Table 3: pB-ALL genotype and phenotype of Sca1-BCR-ABLp190+Pax5+/- and Sca1-BCR-ABLp190 mice.


German Cancer Aid

Translational Oncology Program

German Jose Carreras Foundation

Hochschule Bonn-Rhein-Sieg


Wellcome Trust

Leukemia and Lymphoma Society

Norman and Sadie Lee Foundation

Dr. Ralph and Marian Falk Medical Research Trust

Cancer Research Institute through a Clinic and Laboratory Integration Program

California Institute for Regenerative Medicine (CIRM)

German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany



Instituto de Salud Carlos III

ISCIII- Plan de Ayudas IBSAL 2015 Proyectos Integrados

Junta de Castilla y León

European Union's Seventh Framework Programme

German Carreras Foundation

Ministerio de Economía y Competitividad

FSE-Conserjería de Educación de la Junta de Castilla y León

Deutsche Forschungsgemeinschaft (DFG) fellowship



Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here, we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL–negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/− mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch toward increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR-ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells.Significance: Loss of Pax5 drives metabolic reprogramming, which together with Sca1-restricted BCR-ABL expression enables leukemic transformation. Cancer Res; 78(10); 2669–79. ©2018 AACR.