PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia

McRae, Helen M.; Garnham, Alexandra L.; Hu, Yifang; Witkowski, Matthew T; Corbett, Mark; Dixon, Mathew P.; May, Rose E.; Sheikh, Bilal N.; Chiang, William; Kueh, Andrew J.; Nguyen, Tracy; Man, Kevin; Gloury, Renee; Aubrey, Brandon J.; Policheni, Antonia N.; Rago, Ladina Di; Alexander, Warren S.; Gray, Daniel H.D.; Hawkins, Edwin D.; Wilcox, Stephen; Gécz, Jozef; Kallies, Axel; McCormack, Matthew P.; Smyth, Gordon K.; Voss, Anne K.; Thomas, Tim

doi:10.1182/blood-2018-07-860726

Cited by 37 publications

(42 citation statements)

References 59 publications

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“…While PHF6 mutations were always accompanied by NOTCH1 alterations in Cluster 1, 3/5 PHF6 -mutated IALs (1/3 T-ALL and 2/2 AML) were NOTCH1 wild-type. This pattern was also reported in MPAL (35, 50), and suggests that the leukemic phenotype of PHF6 mutation may correlate with co-expression of other oncogenes, as shown for TLX3 (51). Interestingly, PHF6 has been shown to regulate B/T lineage plasticity, at least on a BCR-ABL leukemic background (52).…”

Section: Discussionsupporting

confidence: 71%

A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis

Bond

Krzywon²,

Lhermitte

et al. 2019

Preprint

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34Classification of acute lymphoblastic and myeloid leukemias (ALL and AML) remains 35 heavily based on phenotypic resemblance to normal hematopoietic precursors. This 36 framework can provide diagnostic challenges for immunophenotypically heterogeneous 37 immature leukemias, and ignores recent advances in understanding of developmental 38 multipotency of diverse normal hematopoietic progenitor populations that are 39 identified by transcriptional signatures. We performed transcriptional analyses of a 40 large series of acute myeloid and lymphoid leukemias and detected significant overlap 41 in gene expression between cases in different diagnostic categories. Bioinformatic 42 classification of leukemias along a continuum of hematopoietic differentiation identified 43 leukemias at the myeloid/T-lymphoid interface, which shared gene expression 44 programs with a series of multi or oligopotent hematopoietic progenitor populations, 45 including the most immature CD34+CD1a-CD7-subset of early thymic precursors. 46Within these interface acute leukemias (IALs), transcriptional resemblance to early 47 lymphoid progenitor populations and biphenotypic leukemias was more evident in 48 cases originally diagnosed as AML, rather than T-ALL. Further prognostic analyses 49 revealed that expression of IAL transcriptional programs significantly correlated with 50 poor outcome in independent AML patient cohorts. Our results suggest that traditional 51 binary approaches to acute leukemia categorization are reductive, and that 52 identification of IALs could allow better treatment allocation and evaluation of 53 therapeutic options.54 55 3 Introduction: 56 Successful management of acute leukemia is underpinned by accurate diagnostic 57 classification, which provides a basis for treatment allocation, risk stratification and 58 implementation of targeted therapies (1). Although knowledge of the molecular 59 landscape of leukemia has increased enormously over the past decades, contemporary 60 classification remains heavily predicated on simple immunophenotypic resemblance to 61 either myeloid or lymphoid normal hematopoietic precursors (2). While this system has 62 historically been successful, some leukemia categories provide specific diagnostic and 63 therapeutic challenges. The current World Health Organization (WHO) classification (2) 64 recognizes acute leukemias of ambiguous lineage that either lack lineage-specific 65 markers (acute undifferentiated leukemias, AUL) or express a mixture of myeloid and 66 lymphoid antigens (mixed phenotype acute leukemias, MPAL). There is little consensus 67 on the best treatment approaches for these patients, and prognosis is usually poor (3-68 5). 69 This framework also poses difficulties for some cases of T-acute lymphoblastic leukemia 70 (T-ALL) and acute myeloid leukemia (AML). T-ALL can be subclassified by 71 immunogenotypic and phenotypic resemblance to either immature/ early thymic 72 precursor (ETP), early cortical or late cortical normal T-progenitor equivalents (6, 7). 73 However, ...

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Section: Discussionsupporting

confidence: 71%

A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis

Bond

Krzywon²,

Lhermitte

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…While PHF6 mutations were always accompanied by NOTCH1 alterations in Cluster 1, 3/5 PHF6 -mutated IALs (1/3 T-ALL and 2/2 AML) were NOTCH1 wild-type. This pattern was also reported in MPAL [ 35 , 49 ], and suggests that the leukemic phenotype of PHF6 mutation may correlate with co-expression of other oncogenes, as shown for TLX3 [ 50 ]. Interestingly, PHF6 has been shown to regulate B/T lineage plasticity, at least on a BCR-ABL leukemic background [ 51 ].…”

Section: Discussionsupporting

confidence: 64%

A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis

et al. 2020

View full text Add to dashboard Cite

Classification of acute lymphoblastic and myeloid leukemias (ALL and AML) remains heavily based on phenotypic resemblance to normal hematopoietic precursors. This framework can provide diagnostic challenges for immunophenotypically heterogeneous immature leukemias, and ignores recent advances in understanding of developmental multipotency of diverse normal hematopoietic progenitor populations that are identified by transcriptional signatures. We performed transcriptional analyses of a large series of acute myeloid and lymphoid leukemias and detected significant overlap in gene expression between cases in different diagnostic categories. Bioinformatic classification of leukemias along a continuum of hematopoietic differentiation identified leukemias at the myeloid/T-lymphoid interface, which shared gene expression programs with a series of multi or oligopotent hematopoietic progenitor populations, including the most immature CD34+CD1a−CD7− subset of early thymic precursors. Within these interface acute leukemias (IALs), transcriptional resemblance to early lymphoid progenitor populations and biphenotypic leukemias was more evident in cases originally diagnosed as AML, rather than T-ALL. Further prognostic analyses revealed that expression of IAL transcriptional programs significantly correlated with poor outcome in independent AML patient cohorts. Our results suggest that traditional binary approaches to acute leukemia categorization are reductive, and that identification of IALs could allow better treatment allocation and evaluation of therapeutic options.

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“…PHF6 mutations have not been observed thus far in non-hematopoietic malignancies, suggesting a crucial role in normal hematopoiesis. It is already shown that loss of PHF6 expression in B-ALL cells can induce a partial switch toward the T cell lineage ( Soto-Feliciano et al, 2017 ) and additional recent data support a role for PHF6 in murine hematopoietic stem and progenitor cell homeostasis ( McRae et al, 2019 ) and renewal ( Miyagi et al, 2019 ).…”

Section: Introductionmentioning

confidence: 85%

PHF6 Expression Levels Impact Human Hematopoietic Stem Cell Differentiation

Loontiens

Dolens

Strubbe

et al. 2020

Front. Cell Dev. Biol.

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Transcriptional control of hematopoiesis involves complex regulatory networks and functional perturbations in one of these components often results in malignancies. Loss-of-function mutations in PHF6 , encoding a presumed epigenetic regulator, have been primarily described in T cell acute lymphoblastic leukemia (T-ALL) and the first insights into its function in normal hematopoiesis only recently emerged from mouse modeling experiments. Here, we investigated the role of PHF6 in human blood cell development by performing knockdown studies in cord blood and thymus-derived hematopoietic precursors to evaluate the impact on lineage differentiation in well-established in vitro models. Our findings reveal that PHF6 levels differentially impact the differentiation of human hematopoietic progenitor cells into various blood cell lineages, with prominent effects on lymphoid and erythroid differentiation. We show that loss of PHF6 results in accelerated human T cell development through reduced expression of NOTCH1 and its downstream target genes. This functional interaction in developing thymocytes was confirmed in vivo using a phf6 -deficient zebrafish model that also displayed accelerated developmental kinetics upon reduced phf6 or notch1 activation. In summary, our work reveals that appropriate control of PHF6 expression is important for normal human hematopoiesis and provides clues towards the role of PHF6 in T-ALL development.

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PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia

Cited by 37 publications

References 59 publications

A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis

A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis

A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis

PHF6 Expression Levels Impact Human Hematopoietic Stem Cell Differentiation

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