Targeting the PI3K/Akt/mTOR pathway may have pro-apoptotic and antiproliferative effects on hematological malignancies. Furthermore, modulation of miRNA can be used as a novel therapeutic approach to regulate the PI3K/Akt/mTOR pathway. However, both aspects require further clinical studies.

Tumor cells are able to attract mesenchymal stem cells (MSCs) to primary tumor site. On the other hand, MSCs secrete various factors to attract tumor cells towards BM. In this review, in addition to assessment of MSCs function at tumor sites and their impact on growth and metastasis of tumor cells, the importance of MSC in attraction of malignant cells to BM and their involvement in drug resistance of tumor cells have also been studied. Relevant literature was identified by a PubMed search (2000-2015) of English-language literature using the terms mesenchymal stem cells, cancer cell, metastasis, and tumor microenvironment. MSCs migrate towards tumor microenvironment and are involved in both pro-tumorigenic and antitumorigenic functions. The dual function of MSCs at tumor sites is dependent upon a variety of factors, including the type and origin of MSCs, the cancer cell line under study, in vivo or in vitro conditions, the factors secreted by MSCs and interactions between MSCs, host immune cells and cancer cells. Therefore, MSCs can be regarded both as friends and enemies of cancer cells. Although the role of a number of pathways, including IL-6/STAT3 pathway, has been indicated in controlling the interaction between MSCs and tumor cells, other mechanisms by which MSCs can control the tumor cells are not clear yet. A better understanding of these mechanisms through further studies can determine the exact role of MSCs in cancer progression and identify them as important therapeutic agents or targets.

The bone marrow (BM) niche is a specific physiological environment for hematopoietic and non-hematopoietic stem cells (HSCs). Several signaling pathways (including Wnt/β-catenin) regulate various aspects of stem cell growth, function and death in the BM niche. In addition, the canonical Wnt pathway is crucial for directing self-renewal and differentiation as important mechanisms in many types of stem cells. We review the role of the Wnt/β-catenin pathway in the BM niche and its importance in stem cells. Relevant literature was identified by a PubMed search (1997-2014) of English-language literature by using the following keywords: BM niche, Wnt/β-catenin signaling, osteoblast, osteoclast and bone disease. The Wnt/β-catenin pathway regulates the stability of the β-catenin proto-oncogene. The stabilized β-catenin then translocates to the nucleus, forming a β-catenin-TCF/LEF complex regulating the transcription of specific target genes. Stem cells require β-catenin to mediate their response to Wnt signaling for maintenance and transition from the pluripotent state during embryogenesis. In adult stem cells, Wnt signaling functions at various hierarchical levels to contribute to the specification of the diverse tissues. Aberrant Wnt/β-catenin signaling and its downstream transcriptional regulators are observed in several malignant stem cells and human cancers. Because Wnt signaling can maintain stem cells and cancer cells, the ability to modulate the Wnt pathway either positively or negatively may be of therapeutic relevance. The controlled activation of Wnt signaling might allow us to enhance stem and progenitor cell activity when regeneration is needed.

Acute myeloid leukemia (AML) is a heterogeneous disorder among hematologic malignancies. Several genetic alterations occur in this disease, which cause proliferative progression, reducing differentiation and apoptosis in leukemic cells as well as increasing their survival. In the genetic study of AML, genetic translocations, gene overexpression, and mutations effective upon biology and pathogenesis of this disease have been recognized. Proto-oncogenes and tumor suppressor genes, which are important in normal development of myeloid cells, are involved in the regulation of cell cycle and apoptosis, undergo mutation in this type of leukemia, and are effective in prognosis of AML subtypes. This review deals with these genes, the assessment of which can be important in the diagnosis and prognosis of patients as well as therapeutic outcome.

Twist proteins are members of basic helix-loop-helix family and are major regulators of embryogenesis. In adult humans, Twist proteins are mainly expressed in precursor cells, including myogenic, osteoblastic, chondroblastic and myelomonocytic lineages, maintaining their undifferentiated state. In addition, they play important roles in lymphocyte function and maturation. Recently, several studies have reported regulatory roles for Twist in the function and development of hematopoietic cells as well as in survival and development of numerous hematological malignancies. It is activated by numerous signal transduction pathways, including Akt, nuclear factor κB, Wnt, signal transducer and activator of transcription 3, mitogen-activated protein kinase and Ras signaling. Activated Twist has an anti-apoptotic role and protects cancer cells from apoptotic cell death. In addition, overexpression of Twist promotes the process of epithelial-mesenchymal transition, which has an essential role in cancer metastasis. Hereby, we review the aberrant expression of Twist in hematopoietic malignancies such as leukemias, lymphomas and myelodysplastic syndrome, which is related with poor prognosis and drug resistance in these disorders. Inactivation of Twist by small RNAs technology or chemotherapeutic inhibitors targeting Twist and upstream or downstream molecules of Twist signaling pathways may be helpful in management of disease to improve treatment strategies in malignancies.

Pax5 transcription factor, also known as B-cell specific activator protein (BSAP), plays a dual role in the hematopoietic system. Pax5 expression is essential in B-cell precursors for normal differentiation and maturation of B-cells. On the other hand, it inhibits the differentiation and progress toward other lineages. The expression of this factor is involved in several aspects of B-cell differentiation, including commitment, immunoglobulin gene rearrangement, BCR signal transduction and B-cell survival, so that the deletion or inactivating mutations of Pax5 cause cell arrest in Pro-B-cell stage. In recent years, point mutations, deletions and various rearrangements in Pax5 gene have been reported in several types of human cancers. However, no clear relationship has been found between these aberrations and disease prognosis. Specific expression of Pax5 in B-cells can raise it as a marker for the diagnosis and differentiation of B-cell leukemias and lymphomas as well as account for remission or relapse. Extensive studies on Pax5 along with other genes and immunomarkers are necessary for decisive results in this regard.

BRAF is a serine/threonine kinase with a regulatory role in the mitogen-activated protein kinase (MAPK) signaling pathway. A mutation in the RAF gene, especially in BRAF protein, leads to an increased stimulation of this cascade, causing uncontrolled cell division and development of malignancy. Several mutations have been observed in the gene coding for this protein in a variety of human malignancies, including hairy cell leukemia (HCL). BRAF V600E is the most common mutation reported in exon15 of BRAF, which is observed in almost all cases of classic HCL, but it is negative in other B-cell malignancies, including the HCL variant. Therefore it can be used as a marker to differentiate between these B-cell disorders. We also discuss the interaction between miRNAs and signaling pathways, including MAPK, in HCL. When this mutation is present, the use of BRAF protein inhibitors may represent an effective treatment. In this review we have evaluated the role of the mutation of the BRAF gene in the pathogenesis and progression of HCL.

Background: Cancer-related Fatigue (CRF) is one of the most common complications of acute myeloid leukemia (AML) and its related therapies. It can influence all physical and psychological aspects of the patient's life. Also, it is believed that exercise can improve CRF in patients with cancer. Objective: This study aimed to investigate the effect of the walking exercise program on CRF in patients with AML undergoing chemotherapy. Methods: In this quasi-experimental study with a pre-and post-test design, 50 patients with AML undergoing chemotherapy were selected using a convenience sampling method at a teaching hospital in an urban area of Iran. The intervention included daily 30 minutes of planned walking for ten days. Data was collected using a demographic data form and the Brief Fatigue Inventory, which were filled out before the intervention, and on the fifth and tenth days of the intervention. Findings: Statistically significant differences were reported in the reduction of CRF on the fifth day and tenth day of the intervention (p <0.001). Conclusions: The planned walking intervention can be used as an easy and low-cost method for reducing CRF in patients with leukemia.