Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression

Abstract

Key Points• In CML, early alterations of the BMP pathway are involved in the survival of hypersensitive LSCs and the expansion of myeloid progenitors.• The leukemic niche provides higher concentrations of BMP2 and BMP4 that fuel a permanent and autonomous pool of leukemic progenitors.Leukemic stem cells in chronic phase chronic myelogenous leukemia (CP-CML) are responsible for disease persistence and eventual drug resistance, most likely because they survive, expand, and are sustained through interactions with their microenvironment. Bone morphogenetic proteins 2 (BMP2) and 4 (BMP4) regulate the fate and proliferation of normal hematopoietic stem cells, as well as interactions with their niche. We show here that the intrinsic expression of members of the BMP response pathway are deregulated in CML cells with differences exhibited in mature (CD34 2 ) and immature (CD34 1 ) compartments. These changes are accompanied by altered functional responses of primitive leukemic cells to BMP2 and BMP4 and strong increases in soluble BMP2 and BMP4 in the CML bone marrow. Using primary cells and a cell line mimicking CP-CML, we found that myeloid progenitor expansion is driven by the exposure of immature cells overexpressing BMP receptor Ib to BMP2 and BMP4. In summary, we demonstrate that deregulation of intracellular BMP signaling in primary CP-CML samples corrupts and amplifies their response to exogenous BMP2 and BMP4, which are abnormally abundant within the tumor microenvironment. These results provide new insights with regard to leukemic stem cell biology and suggest possibilities for the development of novel therapeutic tools specifically targeting the CML niche. (Blood. 2013;122(23):3767-3777) IntroductionChronic myelogenous leukemia (CML) likely arises from a stem cell (SC) transformation induced by the formation of the BCR-ABL oncogene. Without treatment, the disease evolves to an inexorable fatal blast crisis. Until recently, imatinib has become the gold standard for chronic phase (CP)-CML care.1 However, some discrete Philadelphia-positive (Ph 1 ) leukemic SCs (LSCs) may be insensitive to tyrosine kinase inhibitors (TKIs) 2-4 and, therefore, sustain detectable disease for many years. None of the therapeutic agents available to date seem to eradicate the undifferentiated BCR-ABL 1 cells that serve as a reservoir for additional oncogenic events leading to disease progression, 2,4-6 and they require continued treatment. 7,8 Therefore, CML represents a unique model to study LSC biology and to elucidate some of the mechanisms of therapeutic resistance.Complete elimination of CML clones has rarely been achieved by TKIs because of the development of a variety of cell-intrinsic and cell-extrinsic protective mechanisms. Extrinsic mechanisms are supported by the bone marrow (BM) microenvironment, the so-called "leukemic niche." Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-b superfamily and regulate hematopoietic SC fate both directly at various stages of SC differentiation 9-11 and indir...

ZNF423: Transcriptional modulation in development and cancer

“…5 BMP signaling regulates proliferation, differentiation, and maintenance of the hematopoietic stem cell pool [62][63][64][65] and it has been inferred that its deregulation is associated with hematopoietic disorders. 66 Acute leukemia was not induced by sole expression of ZNF423 in human hematopoietic stem cells in a mouse model system, which is in line with the notion of a multistep leukemogenic process. 5,48,57,67 However, ZNF423 critically interferes with B-cell differentiation and functionally recapitulates genomic alterations in B-cell differentiation factors, which are associated with an adverse outcome depending on their cumulative number.…”

Implication of the Autologous Immune System in BCR–ABL Transcript Variations in Chronic Myelogenous Leukemia Patients Treated with Imatinib

“…The microenvironment of the leukemic cells is known to have a strong influence on both healthy and leukemic cells (31,32), but is not included in our model. In addition, we do not account for patients who do not properly or regularly take their drugs, which is known to be an important factor (33).…”

Osteogenic Potential of Mesenchymal Stromal Cells Contributes to Primary Myelofibrosis

“…The increased osteogenic potential of primary myelofibrosis-MSCs associated with increased fibrosis contrasts with data from Avanzini and colleagues reporting a decreased osteogenic ability in MPN-MSCs (8) but fits with the osteomyelosclerosis observed in patients. Besides their role in osteogenesis, TGFb1 and BMPs are involved in regulation of HSC dormancy and therefore, they may contribute to leukemic stem cell maintenance as recently reported in another myeloproliferative neoplasm such as chronic myeloid leukemia (48). Taking into account the cross-influence between the bone marrow extracellular matrix composition and the …”