Identification of T-lymphocytic leukemia–initiating stem cells residing in a small subset of patients with acute myeloid leukemic disease

Abstract

Xenotransplantation of acute myeloid leukemia (AML) into immunodeficient mice has been critical for understanding leukemogenesis in vivo and defining selfrenewing leukemia-initiating cell subfractions (LICs). Although AML-engraftment capacity is considered an inherent property of LICs, substrains of NOD/SCID mice that possess additional deletions such as the IL2R␥c null (NSG) have been described as a more sensitive recipient to assay human LIC function. Using 23 AML-patient samples, 39% demonstrated no detectable engraftment in NOD/SCID and were categorized as AMLs devoid of LICs. However, 33% of AML patients lacking AML-LICs were capable of engrafting NSG recipients, but produced a monoclonal T-cell proliferative disorder similar to T-ALL. These grafts demonstrated selfrenewal capacity as measured by in vivo serial passage and were restricted to CD34-positive fraction, and were defined as LICs. IntroductionOne of the most provocative observations in the field of human cancer biology has been the demonstration that some types of cancer are initiated and sustained by a rare population of cells that possess stem cell characteristics. 1,2 These cells, termed cancer stem cells (CSCs), are best described in human acute myeloid leukemia (AML), representing an aggressive hematopoietic malignancy where an impaired differentiation program results in the accumulation of immature myeloid blasts. 3,4 The identification of a rare self-renewing cell population termed leukemia-initiating cells (LICs) capable of initiating and sustaining growth of human leukemia was based on transplantation of primary AML cells into immunodeficient NOD/SCID mice. 3,4 LICs can be prospectively isolated based on surface-marker expression in the BM and peripheral blood of AML patients. 4,5 Because of their characteristics that include self-renewal and disease initiation, it has been proposed that these cells possess "stem cell-like" properties and are responsible for the occurrence of minimal residual disease (MRD) and related leukemia relapse. 6-9 As such, characterization of the LICs in human leukemia has become an important pursuit for understanding the human leukemogenic process to design new therapies capable of targeting LICs with the overarching goal of eradicating the disease.Although, AML-derived LICs are defined functionally in xenotransplantation models, different strains of immunodeficient mice have been studied to detect human AML-LICs. Initially SCID recipients 3 and subsequently NOD/SCID mice 4 have been widely used to model human leukemia and define the LIC fraction that is restricted to the CD34 ϩ population. 3,4 Further modification of the NOD/SCID, especially the absence of ␤2 microglobulin in NOD/SCID ␤2 Ϫ/Ϫ mice lacking the expression of MHC class I, diminishes host innate response and permits enhanced human leukemia engraftment. 10 More recently, IL2R␥c (CD132) deficient NOD/SCID mice have impaired signaling through multiple cytokine receptors, resulting in blocked NK-cell development and severely decreased immune response, ...

Spleens of myelofibrosis patients contain malignant hematopoietic stem cells

“…These MF-SCs are capable in selected patients of producing limited numbers of B and T cells belonging to the malignant clone, but in large part this potential to generate malignant T cells and B cells is silenced as hematopoietic commitment and differentiation proceeds. The potential of a stem cell from a myeloid malignancy to generate not only myeloid but also lymphoid cells has not been previously reported to such an extensive degree (29,30).…”

A clinically relevant population of leukemic CD34+CD38− cells in acute myeloid leukemia

“…[8][9][10][11] However, the mouse engraftment assay may more accurately reflect the proliferative potential of the leukemic cells 13 and/or their interaction with the mouse microenvironment, 25 than it does their role in Figure 1D. (B) An AML patient (patient 1) with Inv16 AML, demonstrating the "MRD" pattern while still in CR; the circled CD34 ϩ CD38 Ϫ ALDH int population was 95% leukemic by FISH. The comparison diagnostic pattern is shown in Figure 1C.…”

Dysregulated signaling pathways in the development of CNTRL-FGFR1–induced myeloid and lymphoid malignancies associated with FGFR1 in human and mouse models

“…12 These results argue against NSG strains being unable to support Tlymphopoiesis after receiving transplants with human cells 41 and supports other observation of human HSC engraftment in NSG mice. 40,42 As such, the NSG model can be used to study leukemogenesis in myeloid and T-and B-lymphoid lineages.…”