Loss of CD44 attenuates aberrant GM-CSF signaling in Kras G12D hematopoietic progenitor/precursor cells and prolongs the survival of diseased animals

J Du, Y Liu, B Meline, G Kong, LX Tan, JC Lo, J Wang… - Leukemia, 2013 - nature.com
J Du, Y Liu, B Meline, G Kong, LX Tan, JC Lo, J Wang, E Ranheim, L Zhang, YI Chang
Leukemia, 2013nature.com
CD44 is a transmembrane glycoprotein expressed on the surface of many cell types
including the majority of myeloid cells and early thymic T-cell progenitors. 1 As a cell
adhesion molecule, CD44 is differentially required for the adhesion and mobility of different
leukemia-initiating cells. In animal models of BCR-ABL-induced human hematopoietic
malignancies, CD44 is required for the homing and engraftment of chronic myeloid leukemia-
initiating cells, but is dispensable for the engraftment of B-cell lymphoblastic leukemia …
CD44 is a transmembrane glycoprotein expressed on the surface of many cell types including the majority of myeloid cells and early thymic T-cell progenitors. 1 As a cell adhesion molecule, CD44 is differentially required for the adhesion and mobility of different leukemia-initiating cells. In animal models of BCR-ABL-induced human hematopoietic malignancies, CD44 is required for the homing and engraftment of chronic myeloid leukemia-initiating cells, but is dispensable for the engraftment of B-cell lymphoblastic leukemia-initiating cells. 2 In contrast, in an animal model of human acute myeloid leukemia, a CD44-activating antibody eradicates leukemia-initiating cells partially by interfering with their interaction with the microenvironment. 3 CD44 is also an important regulator of cell signaling and regulates signaling cascades in various ways. 1 For example, CD44 can provide specialized platforms for growth factors and matrix metalloproteinases, act as a coreceptor in many receptor complexes and/or organize signaling cascades through association with cytoskeleton. During tumorigenesis, various signals have been implicated in regulating CD44 expression and/or its alternative splicing. A positive-feedback loop has been identified to couple the activation of Ras/ERK signaling and induction of CD44 expression, in particular expression of its splicing variant v6. 4 Ras signaling promotes CD44v6 expression, and in turn CD44v6 sustains late Ras signaling. Consistent with this finding, we and others previously reported that CD44 is invariably overexpressed in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by endogenous oncogenic Kras (Kras G12D) or oncogenic Nras. 5–7 Under physiological conditions, CD44 is only transiently expressed in early thymic T-cell progenitors at the CD4, CD8-double negative 1 (DN1) and DN2 stages. However, in T-ALL patients, CD44 is often expressed in the tumor T cells. Expression of CD44 correlates with increased numbers of circulating blasts, as well as tissue infiltration, 8 and is a negative prognostic factor. 9 Activation of CD44 enhances DNA repair and thus protects T-ALL cells from chemo/radiation therapy-induced apoptosis. Consistent with this finding, blocking of the CD44 function by IM7 antibody sensitizes T-ALL cells to dexamethasoneinduced apoptosis. Despite the apparently necessary role of CD44 in some types of cancers, CD44 is dispensable in normal cells as mice develop and survive well in the absence of CD44. 10 This makes CD44 an attractive target for treating CD44ū cancers. Given the important role of CD44 in homing and engraftment of tumor cells, as well as in modulating cytokine signaling, we asked whether and how CD44 deficiency affects Kras G12D-induced hematopoietic malignancies. To address these questions, we generated LSL Kras G12D/ū; Mx1-Cre mice and LSL Kras G12D/ū; Mx1-Cre; CD44Ā/Ā mice (Figure S1A). Administration of polyinosinic-polycytidylic acid (pI-pC) in these compound mice induces expression of Kras G12D. We refer to these pI-pC-treated compound mice as Kras G12D and Kras G12D; CD44Ā/Ā mice, respectively, and pI-pC-treated Mx1-Cre or wild-type mice as control mice throughout this paper. After acute induction of Kras G12D expression in whole bone marrow cells, both Kras G12D and Kras G12D; CD44Ā/Ā mice showed marked splenomegaly, which is characteristic of myeloproliferative neoplasm (MPN)(Figure 1a and Figure S1B). However, the average spleen weight of Kras G12D; CD44Ā/Ā mice was significantly lower than that of Kras G12D mice, suggesting that CD44 deficiency attenuates but does not completely prevent acute …
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