Convergent genetic aberrations in murine and human T lineage acute lymphoblastic leukemias

Abstract

The lack of predictive preclinical models is a fundamental barrier to translating knowledge about the molecular pathogenesis of cancer into improved therapies. Insertional mutagenesis (IM) in mice is a robust strategy for generating malignancies that recapitulate the extensive inter- and intra-tumoral genetic heterogeneity found in advanced human cancers. While the central role of "driver" viral insertions in IM models that aberrantly increase the expression of proto-oncogenes or disrupt tumor suppressors has been appreciated for many years, the contributions of cooperating somatic mutations and large chromosomal alterations to tumorigenesis are largely unknown. Integrated genomic studies of T lineage acute lymphoblastic leukemias (T-ALLs) generated by IM in wild-type (WT) and Kras mutant mice reveal frequent point mutations and other recurrent non-insertional genetic alterations that also occur in human T-ALL. These somatic mutations are sensitive and specific markers for defining clonal dynamics and identifying candidate resistance mechanisms in leukemias that relapse after an initial therapeutic response. Primary cancers initiated by IM and resistant clones that emerge during in vivo treatment close key gaps in existing preclinical models, and are robust platforms for investigating the efficacy of new therapies and for elucidating how drug exposure shapes tumor evolution and patterns of resistance.

Integrated Genomic Analyses Identify High-Risk Factors and Actionable Targets in T-Cell Acute Lymphoblastic Leukemia

“…This, together with previously reported sensitivities of PTEN mutated T-ALLs to anti-PI3K targeted therapies [30,50,51,59], suggest that RAS pathway and PTEN mutations may serve as both prognostic indicators and actionable drug targets for more than 30% T-ALLs. Previous study also suggested that the combination of PI3K inhibitor and MEKi inhibitor was an effective treatment strategy in relapse T-ALLs [60]. If we narrowly define those patients who had died or relapsed within three years as high-risk patients, then 43% of them had potential actionable targets (Supplementary Table 9).…”

Opposing effects of KDM6A and JDP2 on glucocorticoid sensitivity in T-ALL

“…In this T-ALL model, retroviral insertions cooperate with somatic mutations in known human oncogenes and tumor suppressors such as Notch1 and Ikzf1 . 10 , 11 To identify the mechanisms of GC resistance, we transplanted 10 independent leukemias into recipient mice and treated them with vehicle, DEX, or DEX/GDC-0941 until relapse ( Figure 1 A). 2 In T-ALL 8633, DEX treatment significantly prolonged survival, which was not enhanced by cotreatment with GDC-0941 ( Figure 1 B).…”

Integrated genomic analyses identify high-risk factors and actionable targets in T-cell acute lymphoblastic leukemia

“…Previous study also suggested that the combination of PI3K inhibitor and MEKi inhibitor was an effective treatment strategy in relapse T-ALLs. 61 If we narrowly define those who had died or relapsed three years as high-risk patients, then 43% of them had potential actionable targets (Supplementary Table 9, http://links.lww.com/BS/A42). Further pre-clinical and clinical investigations are required test these targets.…”

“…This, together with previously reported sensitivities of PTEN mutated T-ALLs to anti-PI3K targeted therapies, 31,43,52,60 suggest that RAS pathway and PTEN mutations may serve as both prognostic indicators and actionable drug targets for more than 30% T-ALLs. Previous study also suggested that the combination of PI3K inhibitor and MEKi inhibitor was an effective treatment strategy in relapse T-ALLs 61 . If we narrowly define those patients who had died or relapsed within three years as high-risk patients, then 43% of them had potential actionable targets (Supplementary Table 9, http://links.lww.com/BS/A42).…”