Clonal evolution of preleukemic hematopoietic stem cells in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogenous disease according to morphology, immunophenotype, and genetics. The retained capacity of differentiation is the basis for the phenotypic classification of the bulk population of leukemic blasts and the identification of distinct subpopulations. Within the hierarchy of hematopoietic development and differentiation it is still unknown at which stage the malignant transformation occurs. It was our aim to analyze the potential involvement of cells with the immunophenotype of pluripotent stem cells in the leukemic process by the use of cytogenetic and cell sorting techniques. Cytogenetic analyses of bone marrow aspirates were performed in 13 patients with AML (11 de novo and 2 secondary) and showed karyotype abnormalities in 10 cases [2q+, +4, 6p, t(6:9), 7, +8 in 1 patient each and inv(16) in 4 patients each]. Aliquots of the samples were fractionated by fluorescence-activated cell sorting of CD34+ cells. Two subpopulations, CD34+/CD38-(early hematopoietic stem cells) and CD34+/CD38+ (more mature progenitor cells), were screened for karyotype aberations as a marker for leukemic cells. Clonal abnormalities and evaluable metaphases were found in 8 highly purified CD34+/CD38-populations and in 9 of the CD34+/CD38-specimens, respectively. In the majority of cases (CD34+/CD38-, 6 of 8 informative samples; CD34+/CD38+, 5 of 9 informative samples), the highly purified CD34+ specimens also contained cytogenetically normal cells. Secondary, progression-associated chromosomal changes (+8, 12) were identified in the CD34+/CD38-cells of 2 patients. We conclude that clonal karyotypic abnormalities are frequently found in the stem cell-like (CD34+/CD38-) and more mature (CD34+/CD38+) populations of patients with AML, irrespective of the phenotype of the bulk population of leukemic blasts and of the primary or secondary character of the leukemia. Our data suggest that, in AML, malignant transformation as well as disease progression may occur at the level of CD34+/CD38-cells with multilineage potential.

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Megakaryocyte-derived excessive transforming growth factor β1 inhibits proliferation of normal hematopoietic stem cells in acute myeloid leukemia

Experimental Hematology ◽

10.1016/j.exphem.2017.12.010 ◽

2018 ◽

Vol 60 ◽

pp. 40-46.e2 ◽

Cited By ~ 4

Author(s):

Yuemin Gong ◽

Mei Zhao ◽

Wanzhu Yang ◽

Ai Gao ◽

Xiuxiu Yin ◽

...

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Growth Factor ◽

Hematopoietic Stem Cells ◽

Myeloid Leukemia ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Hematopoietic Stem ◽

Acute Myeloid

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Assessing the efficacy of allogeneic hematopoietic stem cells transplantation (allo-HSCT) by analyzing survival end points in defined groups of acute myeloid leukemia patients: A retrospective, multicenter Polish Adult Leukemia Group study

American Journal of Hematology ◽

10.1002/ajh.24113 ◽

2015 ◽

Vol 90 (10) ◽

pp. 904-909 ◽

Cited By ~ 3

Author(s):

Sebastian Grosicki ◽

Jerzy Holowiecki ◽

Kazimierz Kuliczkowski ◽

Aleksander Skotnicki ◽

Andrzej Hellmann ◽

...

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Hematopoietic Stem Cells ◽

Myeloid Leukemia ◽

Hematopoietic Stem ◽

Stem Cells Transplantation ◽

Hematopoietic Stem Cells Transplantation ◽

Adult Leukemia ◽

Leukemia Group ◽

Acute Myeloid

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MicroRNA-29a Is An Oncogene in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v112.11.683.683 ◽

2008 ◽

Vol 112 (11) ◽

pp. 683-683

Author(s):

Christopher Y. Park ◽

Yoon-Chi Han ◽

Govind Bhagat ◽

Jian-Bing Fan ◽

Irving L Weissman ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Stem Cells ◽

Acute Myeloid Leukemia ◽

Hematopoietic Stem Cells ◽

Mirna Expression ◽

Myeloid Leukemia ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract microRNAs (miRNAs) are short, non-protein encoding RNAs that bind to the 3′UTR’s of target mRNAs and negatively regulate gene expression by facilitating mRNA degradation or translational inhibition. Aberrant miRNA expression is well-documented in both solid and hematopoietic malignancies, and a number of recent miRNA profiling studies have identified miRNAs associated with specific human acute myeloid leukemia (AML) cytogenetic groups as well as miRNAs that may prognosticate clinical outcomes in AML patients. Unfortunately, these studies do not directly address the functional role of miRNAs in AML. In fact, there is no direct functional evidence that miRNAs are required for AML development or maintenance. Herein, we report on our recent efforts to elucidate the role of miRNAs in AML stem cells. miRNA expression profiling of AML stem cells and their normal counterparts, hematopoietic stem cells (HSC) and committed progenitors, reveals that miR-29a is highly expressed in human hematopoietic stem cells (HSC) and human AML relative to normal committed progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors is sufficient to induce a myeloproliferative disorder (MPD) that progresses to AML. During the MPD phase of the disease, miR-29a alters the composition of committed myeloid progenitors, significantly expedites cell cycle progression, and promotes proliferation of hematopoietic progenitors at the level of the multipotent progenitor (MPP). These changes are manifested pathologically by marked granulocytic and megakaryocytic hyperplasia with hepatosplenomegaly. Mice with miR-29a-induced MPD uniformly progress to an AML that contains a leukemia stem cell (LSC) population that can serially transplant disease with as few as 20 purified LSC. Gene expression analysis reveals multiple tumor suppressors and cell cycle regulators downregulated in miR-29a expressing cells compared to wild type. We have demonstrated that one of these genes, Hbp1, is a bona fide miR-29a target, but knockdown of Hbp1 in vivo does not recapitulate the miR-29a phenotype. These data indicate that additional genes are required for miR-29a’s leukemogenic activity. In summary, our data demonstrate that miR-29a regulates early events in normal hematopoiesis and promotes myeloid differentiation and expansion. Moreover, they establish that misexpression of a single miRNA is sufficient to drive leukemogenesis, suggesting that therapeutic targeting of miRNAs may be an effective means of treating myeloid leukemias.

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