inv(16) and NPM1mut AMLs engraft human cytokine knock-in mice

Abstract

Favorable-risk human acute myeloid leukemia (AML) engrafts poorly in currently used immunodeficient mice, possibly because of insufficient environmental support of these leukemic entities. To address this limitation, we here transplanted primary human AML with isolated nucleophosmin (NPM1) mutation and AML with inv(16) in mice in which human versions of genes encoding cytokines important for myelopoiesis (macrophage colony-stimulating factor [M-CSF], interleukin-3, granulocyte-macrophage colony-stimulating factor, and thrombopoietin) were knocked into their respective mouse loci. NPM1 AML engrafted with higher efficacy in cytokine knock-in (KI) mice and showed a trend toward higher bone marrow engraftment levels in comparison with NSG mice. inv(16) AML engrafted with high efficacy and was serially transplantable in cytokine KI mice but, in contrast, exhibited virtually no engraftment in NSG mice. Selected use of cytokine KI mice revealed that human M-CSF was required for inv(16) AML engraftment. Subsequent transcriptome profiling in an independent AML patient study cohort demonstrated high expression of M-CSF receptor and enrichment of M-CSF inducible genes in inv(16) AML cases. This study thus provides a first xenotransplantation mouse model for and informs on the disease biology of inv(16) AML.

Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines

“…The use of single separated knockin mice would provide a more precise answer on the impact of each cytokine on engraftment, as demonstrated previously. [10][11][12] Although primary transplantation was effective for most patient samples, secondary transplantation was observed for a limited number of cases. This low efficacy may be the consequence of the expansion of GM-CSF hypersensitive progenitors while engraftment of leukemic stem cells may remain limited in these conditions.…”

The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

“…88 However, in the context of MDS PDX, excessive myeloid stimulatory signals in this mouse line was reported to lead to the rapid exhaustion of malignant stem cells (CD34 1 ) 67 or engraftment of healthy HSPCs. 43 New, improved models expressing human cytokines that are knocked-in to the endogenous mouse loci, namely MITRG or MISTRG (Table 1), have demonstrated engraftment of "favorable risk "AML cases 149 that are notoriously difficult to propagate in vivo and were used to demonstrate the specific dependency of inv16 AMLs on exogenous niche-derived macrophage-CSF signals. 149 The ability of such models to support other myeloid malignancies or AML subtypes remains to be tested. )…”

“…43 New, improved models expressing human cytokines that are knocked-in to the endogenous mouse loci, namely MITRG or MISTRG (Table 1), have demonstrated engraftment of "favorable risk "AML cases 149 that are notoriously difficult to propagate in vivo and were used to demonstrate the specific dependency of inv16 AMLs on exogenous niche-derived macrophage-CSF signals. 149 The ability of such models to support other myeloid malignancies or AML subtypes remains to be tested. ) have recently been generated.…”

Lentiviral Fluorescent Genetic Barcoding for Multiplex Fate Tracking of Leukemic Cells

“…Much effort is, therefore, being directed at better characterizing the AML mutational landscape, mutation-dependent transcriptional programs, and epigenetic signatures within the disease driving leukemic stem cell (LSC) population, which contains the functionally defined leukemia-initiating cells (LICs) 1, 2, 3, 4, 5, 6, 7, 8, 9. In addition, major thrusts of current research are focused on establishing optimized in vitro cultivation systems for primary AML cells, as well as developing de novo AML models 10, 11, 12, 13, 14, 15, 16. With these advances, there is an increasing imperative for functional investigations.…”