Preleukemia and Leukemia-Initiating Cell Activity in inv(16) Acute Myeloid Leukemia

Pulikkan, John Anto; Castilla, Lucio H.

doi:10.3389/fonc.2018.00129

Cited by 12 publications

(19 citation statements)

References 80 publications

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“…Development of CBFB-MYH11 AML is classically explained by a clonal evolution model which is featured with multiple stepwise cooperating mutations. 29,30 The cooperating mutations in CBFB-MYH11 leukemia are supposed to be class I mutations, e.g., mutations in receptor tyrosine kinases that provide proliferation or survival signal to hematopoietic cells, since CBFB-MYH11 is a class II mutation 2 . Using pre-leukemic hematopoietic cells from Cbfb-MYH11 knockin mice, gene expression profiling allowed us to identify 6 most upregulated genes at preleukemic stage.…”

Section: Discussionmentioning

confidence: 99%

Gata2 deficiency delays leukemogenesis while contributing to aggressive leukemia phenotype in Cbfb-MYH11 knockin mice

et al. 2019

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Inversion of chromosome 16 (inv(16)) generates a fusion gene CBFB-MYH11, which is a driver mutation for acute myeloid leukemia (AML). Gene expression profiling suggests that Gata2, a hematopoietic transcription factor, is a top upregulated genes in preleukemic Cbfb-MYH11 knockin mice and is expressed in human inv(16) AML. On the other hand, we have also identified recurrent monoallelic deletions of GATA2 in relapsed human CBF-AML patients. To clarify the role of Gata2 in leukemogenesis by Cbfb-MYH11, we generated conditional Cbfb-MYH11 knockin mice with Gata2 heterozygous knockout. Gata2 heterozygous knockout reduced abnormal myeloid progenitors, which are capable of inducing leukemia in the Cbfb-MYH11 mice. Consequently, Cbfb-MYH11 mice with Gata2 heterozygous knockout developed leukemia with longer latencies than those with intact Gata2. Interestingly, leukemic cells with Gata2 heterozygous knockout gained higher number of mutations and showed more aggressive phenotype in both primary and transplanted mice. Moreover, leukemic cells with Gata2 heterozygous knockout showed higher repopulating capacity in competitive transplantation experiments. In summary, reduction of Gata2 activity affects mutational dynamics of leukemia with delayed leukemia onset in Cbfb-MYH11 knockin mice, but paradoxically results in a more aggressive leukemia phenotype, which may be correlated with leukemia relapse or poor prognosis in human patients. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Section: Discussionmentioning

confidence: 99%

Gata2 deficiency delays leukemogenesis while contributing to aggressive leukemia phenotype in Cbfb-MYH11 knockin mice

et al. 2019

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“…As observed in human leukemia, melanotic tumors, which are composed of aggregated hemocytes and large numbers of abnormal lamellocytes, can appear in Drosophila (Boulet et al, 2018). Leukemic stem/progenitor cells (LSCs) or leukemia-initiating cells (LICs) are the root mediators of leukemia initiation, drug resistance and relapse (Zhou and Xu, 2015;Pulikkan and Castilla, 2018). Reducing the maintenance of LSCs and LICs through niche regulatory signaling is a therapeutic strategy.…”

Section: Drosophila Psc and Leukemiamentioning

confidence: 99%

The Posterior Signaling Center Is an Important Microenvironment for Homeostasis of the Drosophila Lymph Gland

Luo

Jin

2020

Front. Cell Dev. Biol.

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Hematopoiesis is a necessary process for development and immune defense in Drosophila from the embryonic period to adulthood. There are two main stages in this process: the first stage occurs in the head mesoderm during the embryonic stage, and the second occurs in a specialized hematopoietic organ along the dorsal vessel, the lymph gland, during the larval stage. The lymph gland consists of paired lobes, each of which has distinct regions: the cortical zone (CZ), which contains mature hemocytes; the medullary zone (MZ), which contains hematopoietic progenitors; and the posterior signaling center (PSC), which specifically expresses the early B-cell factor (EBF) transcription factor Collier (Col) and the HOX factor Antennapedia (Antp) to form a microenvironment similar to that of the mammalian bone marrow hematopoietic stem cell niche. The PSC plays a key role in regulating hematopoietic progenitor differentiation. Moreover, the PSC contributes to the cellular immune response to wasp parasitism triggered by elevated ROS levels. Two recent studies have revealed that hematopoietic progenitor maintenance is directly regulated by Col expressed in the MZ and is independent of the PSC, challenging the traditional model. In this review, we summarize the regulatory networks of PSC cell proliferation, the controversy regarding PSC-mediated regulation of hematopoietic progenitor differentiation, and the wasp egg infection response. In addition, we discuss why the PSC is an ideal model for investigating mammalian hematopoietic stem cell niches and leukemia.

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“…These mutations were formerly classified into two classes according to the two‐hit hypothesis of leukemogenesis 2,3 . Present evidence changes our understanding of AML evolution from the simple two‐hit model to a multistep process that requires accumulation of several mutations over time 4,5 . Recently, more molecular abnormalities associated with AML have been identified by the use of sequencing approaches like next generation sequencing (NGS) 2,6,7 .…”

Section: Introductionmentioning

confidence: 99%

“…2,3 Present evidence changes our understanding of AML evolution from the simple two-hit model to a multistep process that requires accumulation of several mutations over time. 4,5 Recently, more molecular abnormalities associated with AML have been identified by the use of sequencing approaches like next generation sequencing (NGS). 2,6,7 As many of these mutations have been shown to be associated to good or poor prognosis, the understanding of origin and function of these mutations at an early stage of transformation provides an important knowledge to predict the risk of progression or relapse for individual patients.…”

Section: Introductionmentioning

confidence: 99%

“…2,6,7 As many of these mutations have been shown to be associated to good or poor prognosis, the understanding of origin and function of these mutations at an early stage of transformation provides an important knowledge to predict the risk of progression or relapse for individual patients. 5,8 Data from functional studies suggest that certain mutations may be able to transform normal hematopoietic stem cells (HSC) into leukemic stem cells (LSC). 9,10 The molecular mechanisms of AML evolution; however, are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy‐resistant preleukemic clones

Saeed

Manta

Raffel

et al. 2021

Intl Journal of Cancer

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To acquire a better understanding of clonal evolution of acute myeloid leukemia (AML) and to identify the clone(s) responsible for disease recurrence, we have comparatively studied leukemia‐specific mutations by whole‐exome‐sequencing (WES) of both the leukemia and the nonleukemia compartments derived from the bone marrow of AML patients. The T‐lymphocytes, B‐lymphocytes and the functionally normal hematopoietic stem cells (HSC), that is, CD34+/CD38−/ALDH+ cells for AML with rare‐ALDH+ blasts (<1.9% ALDH+ cells) were defined as the nonleukemia compartments. WES identified 62 point‐mutations in the leukemia compartment derived from 12 AML‐patients at the time of diagnosis and 73 mutations in 3 matched relapse cases. Most patients (8/12) showed 4 to 6 point‐mutations per sample at diagnosis. Other than the mutations in the recurrently mutated genes such as DNMT3A, NRAS and KIT, we were able to identify novel point‐mutations that have not yet been described in AML. Some leukemia‐specific mutations and cytogenetic abnormalities including DNMT3A(R882H), EZH2(I146T) and inversion(16) were also detectable in the respective T‐lymphocytes, B‐lymphocytes and HSC in 5/12 patients, suggesting that preleukemia HSC might represent the source of leukemogenesis for these cases. The leukemic evolution was reconstructed for five cases with detectable preleukemia clones, which were tracked in follow‐up and relapse samples. Four of the five patients with detectable preleukemic mutations developed relapse. The presence of leukemia‐specific mutations in these nonleukemia compartments, especially after chemotherapy or after allogeneic stem cell transplantation, is highly relevant, as these could be responsible for relapse. This discovery may facilitate the identification of novel targets for long‐term cure.

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Preleukemia and Leukemia-Initiating Cell Activity in inv(16) Acute Myeloid Leukemia

Cited by 12 publications

References 80 publications

Gata2 deficiency delays leukemogenesis while contributing to aggressive leukemia phenotype in Cbfb-MYH11 knockin mice

Gata2 deficiency delays leukemogenesis while contributing to aggressive leukemia phenotype in Cbfb-MYH11 knockin mice

The Posterior Signaling Center Is an Important Microenvironment for Homeostasis of the Drosophila Lymph Gland

Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy‐resistant preleukemic clones

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