Epigenetic reversal of hematopoietic stem cell aging in Phf6-knockout mice

Is the philosopher’s stone to rejuvenate blood stem cells an epigenetic regulator?

“…Therefore, although transcription is an important cellular process, post-transcriptional regulation processes are as relevant and should not be overlooked. Furthermore, Phf6 has been implicated in the DNA damage response by previous publications and by the current study 3,8 . Nevertheless, the role of PHF6 and how it controls age-dependent mechanisms remains unknown and it is not resolved by the current study.…”

“…Despite substantial progress and the identification of multiple molecular mechanisms that contribute to the demise of aged HSCs, it has been difficult to restore young-like functions in aged HSCs. In a study published in this issue of Nature Aging, Wendorff and colleagues bring a new fresh breeze into this long-standing puzzle and place epigenetic programming -a somewhat forgotten aspect of aging in the HSC field -into the spotlight 3 . Remarkably, by suppressing a single epigenetic regulator (PHF6) the authors were able to prevent most of the functional decline of HSCs and, more surprisingly, rejuvenate the hematopoietic system in aged mice.…”

Epigenetic Mechanisms in Hematologic Aging and Premalignant Conditions

“…In a recent study, Wendorff et al demonstrated that genetic inactivation of the Phf6 gene mitigated age-associated HSC decline. In addition, LT-HSCs from old Phf6-knockout mice exhibited epigenetic rewiring and altered transcriptional programs, indicating a reduction in genotoxic stress-induced HSC aging [150].…”

PHF6 suppresses self-renewal of leukemic stem cells in AML

“…PHF6 (Plant homeodomain-like finger protein 6) is an X-chromosome gene mutated in a variety of myeloid and lymphoid leukemias. PHF6 protein localizes to the nucleolus and nucleoplasm, and is known to interact with chromatin, but its precise molecular function is poorly understood, with reported roles ranging from cell cycle control (2)(3)(4), DNA repair (4,5), and chromatin and transcriptional regulation (6)(7)(8)(9). Somatic PHF6 mutations were first documented in T-cell acute lymphocytic leukemia (T-ALL), where it was found to be mutated in 38% of patients (10).…”

“…Conditional hematopoietic knockouts using multiple Cre systems have consistently shown minimal alterations to homeostatic hematopoiesis, but striking increases in HSC self-renewal on transplantation, with the ability to engraft recipient marrow beyond five serial transplants without evidence of exhaustion, malignant transformation, or lineage skewing (17–19). Phf6 knockout HSCs from aged mice show transcriptional profiles similar to young HSCs, and deletion of Phf6 from older mice shows a shift towards a younger HSC transcriptome, suggesting that Phf6 loss may counteract HSC aging (5). Combination of Phf6 loss with overexpression of activating mutants of Notch1 ( 18 ) or Jak3 ( 20 ), or overexpression of wild-type Tlx3 ( 17 ) has been shown to cause T-ALL acceleration, while transgenic crosses of Phf6 deletion with Idh2 mutation produce mixed myeloid-lymphoid leukemias (21).…”