Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age

Abstract

In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. Though the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have been incompletely characterized. To elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated immunophenotypic HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged immunophenotypic human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared with young HSC. Gene expression profiling revealed that aged immunophenotypic human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, developmental potential, and gene expression profile of human HSC are similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process.

ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

“…S3F). The ADAR1-mediated myeloid lineage skewing recapitulates qRT-PCR data reported with aged human HSC (37) and the expansion of GMP (34) during progression of CML from CP to BC (Fig. S1F).…”

Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals

“…Consistent with this data, mutations in genes that are often mutated in myeloid malignancy such as TET2, DNMT3A, ASXL1 and JAK2 have also been described in elderly individuals with no evidence of hematological malignancy [5][6][7][8] . Increasing age is accompanied by changes to the hematopoietic stem cell (HSC) compartment, a process known as myeloid shift, with a bias towards the myeloid lineage at the expense of the lymphoid lineage 9 . In addition, acquired skewing of X-chromosome inactivation patterns (XCIP) in elderly women suggests that there is a reduction in stem cell usage over time that might in principle be stochastic or driven by subclinical clonal expansion 10 .…”

B-cell tumor development in Tet2-deficient mice

“…This includes lymphoma but also chronic lymphocytic leukemia (CLL), the most frequent adult leukemia in Western countries with a median age at diagnosis of 72 years. The reasons are not yet fully understood, but they may be due to a modification of hematopoietic stem/ progenitor cell (HSC/P) microenvironment 1 or cell-intrinsic alterations of HSC, 2,3 or both. 4 The importance of cell-intrinsic defects is also supported by the age-related incidence of somatic aberrations detected in the blood cells 5 and in the HSC 6 compartment of individuals devoid of clinical signs of hematological disorder.…”