Targeting of CD44 eradicates human acute myeloid leukemic stem cells

Abstract

The long-term survival of patients with acute myeloid leukemia (AML) is dismally poor. A permanent cure of AML requires elimination of leukemic stem cells (LSCs), the only cell type capable of initiating and maintaining the leukemic clonal hierarchy. We report a therapeutic approach using an activating monoclonal antibody directed to the adhesion molecule CD44. In vivo administration of this antibody to nonobese diabetic-severe combined immune-deficient mice transplanted with human AML markedly reduced leukemic repopulation. Absence of leukemia in serially transplanted mice demonstrated that AML LSCs are directly targeted. Mechanisms underlying this eradication included interference with transport to stem cell-supportive microenvironmental niches and alteration of AML-LSC fate, identifying CD44 as a key regulator of AML LSCs. The finding that AML LSCs require interaction with a niche to maintain their stem cell properties provides a therapeutic strategy to eliminate quiescent AML LSCs and may be applicable to other types of cancer stem cells.

CD44 in hematological neoplasias

“…Therefore they are dependent on finding their specific niche in the BM [99,100]. Together with observed eradication of LIC and reduced repopulation in immune deficient mice [101], this might provide a way of antibody-triggered, CD44-and IL-8/GM-CSF-mediated targeting of AML cells via combined effect of reversed differentiation block and dependency of LIC on their bone marrow niche. Co-culturing of M6-AML TF-1 cells with mouse bone marrow-derived MS-5 cells resulted in increased CD34+ cell number and upregulation of CD44s and CD44v10.…”

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

“…This discovery was followed by several efforts aimed at targeting the hematopoietic cancer stem cell markers, such as CD44 and CD123 in AML [64][65][66][67][68]. Further studies have since been performed by targeting CSCs in several solid tumors such as pancreatic, breast, prostate and colon cancers, melanoma, glioma, hepatocellular carcinoma, and others.…”

“…[72,73], immunomodulation (e.g., CD326, ALDH1 inhibitor) [73,74], sensitizing CSCs to systemic chemotherapy/radiation (e.g., IL4, hyaluronate receptor) [56,75] or inhibiting CSC angiogenesis (e.g., VEGF-R, DLL4) [76][77][78]. An important contribution of CSC research to anti-cancer targeted treatment is that it unveils specific biomarkers which can be targeted in vivo by antibody therapy leading to disrupted tumor growth [60,67,79,80]. Several of these antigens have been known to be expressed in different malignancies, long before their implication as CSC markers.…”

“…Several of these antigens have been known to be expressed in different malignancies, long before their implication as CSC markers. However, their specific targeting was put forward as means to treat human malignancies only following the revelation of their role in signifying the CSC population [67,81,82].…”

Sex differences in the GSK3β-mediated survival of adherent leukemic progenitors

“…In cases of disease remission where elimination of cycling progenitors is achieved, relapses are frequent because of resistant LSCs and the prognosis is poor. The two main options proposed to eradicate LSCs aim at pushing LSCs out of their protective bone marrow niche (Jin et al, 2006;Saito et al, 2010) or killing them by targeting their specific signaling pathways (Guzman et al, 2005;Xu et al, 2005). However, a large number of primary cells from patients are refractive to these treatments, suggesting that new strategies are likely needed to eradicate LSCs.…”