Reticulin fibres anchor leukaemic blasts in the marrow of patients with acute lymphoblastic leukaemia

Nath, Shriram V.; Nicholson, I.; Tapp, Heather; Zola, Heddy; Zannettino, Andrew C.W.; Révész, Tamás

doi:10.1016/j.mehy.2011.05.007

Cited by 11 publications

(10 citation statements)

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“…Noren-Nystrom et al reported that elevated reticulin fibrosis was a common finding in diagnosis trephine biopsy specimens which then returns to normal levels following response to chemotherapy [ 1 ]. We were able to confirm these findings [ 2 ] and also hypothesized that high reticulin fibre content in the marrow ‘anchors’ leukemic cells and is therefore associated with lower blood blast counts [ 3 ].…”

Section: Introductionmentioning

confidence: 65%

“…At the diagnosis of ALL, the bone marrow is characterized by heavy infiltration by leukemic blast cells that occupy most of the marrow. This is accompanied by increased reticulin fibrosis that may serve to ‘anchor’ the leukemic cells in the marrow [ 2 , 3 ]. Moreover, the area occupied by bony trabeculae was reduced in ALL trephine biopsy specimens compared to those from patients with other cancers.…”

Section: Discussionmentioning

confidence: 99%

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Bone Marrow Recovery by Morphometry during Induction Chemotherapy for Acute Lymphoblastic Leukemia in Children

et al. 2015

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Bone marrow architecture is grossly distorted at the diagnosis of ALL and details of the morphological changes that accompany response to Induction chemotherapy have not been reported before. While marrow aspirates are widely used to assess initial response to ALL therapy and provide some indications, we have enumerated marrow components using morphometric analysis of trephine samples with the aim of achieving a greater understanding of changes in bone marrow niches. Morphometric analyses were carried out in the bone marrow trephine samples of 44 children with ALL, using a NanoZoomer HT digital scanner. Diagnostic samples were compared to those of 32 control patients with solid tumors but without marrow involvement. Samples from patients with ALL had significantly increased fibrosis and the area occupied by bony trabeculae was lower than in controls. Cellularity was higher in ALL samples due to leukemic infiltration while the percentage of normal elements such as megakaryocytes, adipocytes, osteoblasts and osteoclasts were all significantly lower. During the course of Induction therapy, there was a decrease in the cellularity of ALL samples at day 15 of therapy with a further decrease at the end of Induction and an increase in the area occupied by adipocytes and the width of sinusoids. Reticulin fibrosis decreased throughout Induction. Megakaryocytes increased, osteoblasts and osteoclasts remained unchanged. No correlation was found between clinical presentation, early response to treatment and morphological changes. Our results provide a morphological background to further studies of bone marrow stroma in ALL.

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Section: Introductionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Bone Marrow Recovery by Morphometry during Induction Chemotherapy for Acute Lymphoblastic Leukemia in Children

et al. 2015

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“…One explanation for this is a tendency to manifest bone marrow fibrosis in patients with ALL. Lymphoblasts and stromal cells secrete lymphokines, which ensure that the leukemic blasts remain in the stromal environment and provide ongoing support for proliferation by inducing myelofibrosis . Bone marrow fibrosis can make aspiration difficult and can even give rise to dry‐tapped specimens and suboptimal conditions for cytogenetic analysis.…”

Section: Discussionmentioning

confidence: 99%

The added values of multiplex reverse transcriptase‐PCR followed by mutation screening in the initial evaluation of acute leukemia

Kim

Cho

Bae

et al. 2016

Int J Lab Hematology

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“…In vivo, vitamin D, in the presence of BCR-ABL + Arf −/− leukemia, also remodeled the bone marrow stroma, inducing expression of Type 1 and V collagens. Others have reported that increased bone marrow reticulin and collagen fibers are associated with malignant diseases and may anchor and trap the leukemic cells in the marrow providing an environment where they become more drug resistant 48 . While this study probed the interaction of 1,25(OH) 2 VD 3 signaling through the co-cultured bone marrow stromal cells, in vivo multiple other cell types in the bone marrow express VDR, including osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

Role of Vitamins A and D in BCR-ABL Arf−/− Acute Lymphoblastic Leukemia

Annu

Cline

Yasuda

et al. 2020

Sci Rep

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The effects of vitamin A and/or vitamin D deficiency were studied in an Arf −/− BcR-ABL acute lymphoblastic leukemia murine model. Vitamin D sufficient mice died earlier (p = 0.003) compared to vitamin D deficient (VDD) mice. Vitamin A deficient (VAD) mice fared worst with more rapid disease progression and decreased survival. Mice deficient for vitamins A and D (VADD) had disease progression similar to VAD mice. Regulatory T cells, previously shown to associate with poor BCR-ABL leukemia control, were present at higher frequencies among CD4 + splenocytes of vitamin A deficient vs. sufficient mice. In vitro studies demonstrated 1,25-dihydroxyvitamin D (1,25(OH) 2 VD 3) increased the number of BCR-ABL ALL cells only when co-cultured with bone marrow stroma. 1,25(OH) 2 VD 3 induced CXCL12 expression in vivo and in vitro in stromal cells and CXCL12 increased stromal migration and the number of BCR-ABL blasts. Vitamin D plus leukemia reprogrammed the marrow increasing production of collagens, potentially trapping ALL blasts. Vitamin A (all trans retinoic acid, ATRA) treated leukemic cells had increased apoptosis, decreased cells in S-phase, and increased cells in G 0 /G 1. ATRA signaled through the retinoid X receptor to decrease BCR-ABL leukemic cell viability. In conclusion, vitamin A and D deficiencies have opposing effects on mouse survival from BCR-ABL ALL. Vitamin D deficiency (VDD) affects an estimated 1 billion people in the world across all ethnicities and age groups 1-3. VDD is an independent risk factor for mortality in the general population 4 and almost 60% of children with malignant diseases have suboptimal vitamin D (VD 3) levels 5. Likewise, the world health organization (WHO) estimated 250 million preschool children are vitamin A deficient (VAD), and this increases the risk of disease and death from severe infections. VAD and VDD are not limited to developing countries. Rather, a recent study found that among 45 people tested in Memphis, TN for vitamin A and vitamin D levels, only two individuals had sufficient levels of both vitamins 6. Vitamin D is a fat-soluble vitamin that not only regulates calcium absorption and bone metabolism, but can also regulate cell proliferation, differentiation and the immune response. The biologically active form of vitamin D, 1,25(OH) 2 VD 3 , binds to the vitamin D receptor (VDR) that heterodimerizes with the retinoid X receptor (RXR). This complex then binds to VDR-RXR response elements in target genes to regulate transcription. VDR is highly expressed in intestine, kidney and bone, but also in normal and neoplastic hematopoietic cells and mesenchymal stem cells in bone marrow 7. 1,25(OH) 2 VD 3 can modify embryonic hematopoietic stem and progenitor cell production 8. 1,25(OH) 2 VD 3 inhibits proliferation of mouse and human myeloid leukemia cells 9 and stimulates myeloid cell differentiation into mature macrophages. Indeed, mice with acute myeloid leukemia (AML) when treated with analogs of 1,25(OH) 2 VD 3 survived longer than the untreated mice 10. Moreover, vitam...

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Reticulin fibres anchor leukaemic blasts in the marrow of patients with acute lymphoblastic leukaemia

Cited by 11 publications

References 12 publications

Bone Marrow Recovery by Morphometry during Induction Chemotherapy for Acute Lymphoblastic Leukemia in Children

Bone Marrow Recovery by Morphometry during Induction Chemotherapy for Acute Lymphoblastic Leukemia in Children

The added values of multiplex reverse transcriptase‐PCR followed by mutation screening in the initial evaluation of acute leukemia

Role of Vitamins A and D in BCR-ABL Arf−/− Acute Lymphoblastic Leukemia

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