Elucidation of mechanism of disease resistance and persistence in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a clonal disorder of the hematopoietic stem cell caused by the BCR-ABL receptor tyrosine kinase. Imatinib mesylate (IM) is an inhibitor of BCR-ABL and has been approved for the treatment of CML. IM is well tolerated and highly efficacious as it induces stable long-term remissions in the vast majority of patients. Despite its efficacy, a still unresolved issue associated with IM therapy is IM resistance in progressed phases of CML and long-term disease persistence. It has been shown that BCR-ABL mRNA and BCR-ABL-positive progenitor and stem cells remain detectable after years of therapy. Based on the BCR-ABL expression analysis and short term IM exposure experiments of IM-naïve, first diagnosis CML precursor cells it has been suggested that BCR-ABL over-expression contributes to a major extend to the incapability of IM to kill and eradicate primitive precursors and CML stem cells. Interestingly, the BCR-ABL expression level in actual persisting CML precursor clones, and the impact of long term IM therapy on the eradication of CML precursors from different bone marrow compartments was never been thoroughly investigated. Here we studied a putative novel IM persistence mechanism by directly investigating in residual BCR-ABL-positive progenitor and stem cell clones in chronic phase CML patients in major molecular remission (MMR) under IM. We could first show that IM not only eliminates BCR-ABL positive cells from both primitive (stem cell containing) and more mature bone marrow precursor compartments but also that, in contrast to the currently proposed model, persisting primitive and mature BCR-ABL positive colony forming clones (CFU) expressed significantly less BCR-ABL than CML CFU isolated from initial diagnosis patients. Indeed, lower BCR-ABL expression reduces IM sensitivity of primary bone marrow progenitors engineered to express BCR-ABL. Whereas high BCR-ABL expression level increased IM responsiveness but also the frequency of BCR-ABL kinase mutation development as the most important IM resistance mechanism. This would explain the low propensity of secondary IM resistance in patients, which do achieve a good molecular remission with IM. Another regulator of BCR-ABL kinase point mutation development has been identified with ICSBP, an interferon regulated gene that was previously found by our group to be downregulated in CML. Lack of ICSBP expression in murine myeloid 32D-BA cells conferred BCR-ABL independent IM resistance and limits the development kinase point mutations. Together, here we described two novel and clinically relevant mechanisms of CML persistence and resistance under IM, which may provide a novel perspective for reassessing treatment strategies aiming at eradicating residual disease in CML and to overcome IM resistance

Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes

Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders.The authors acknowledge funding from the National Health and Medical Research Council (NHMRC), Leukaemia Foundation, Anthony Rothe Foundation, Cancer Institute for New South Wales, South Eastern Area Laboratory Services (SEALS), Wellcome Trust, Leukemia and Lymphoma Society, Medical Research Council (UK), Swedish Cancer Society, Cancer Society in Stockholm, Swedish Research Council, Bloodwise UK, and the NIHR Biomedical Research Centre, Oxford

Prevalence of soil-transmitted helminth infections in HIV patients: a systematic review and meta-analysis

Abstract Soil-transmitted Helminth (STH) infections have been found associated with people living with human immunodeficiency virus (HIV) but little is known about the overall burden of STH coinfection in HIV patients. We aimed to assess the burden of STH infections among HIV patients. Relevant databases were systematically searched for studies reporting the prevalence of soil-transmitted helminthic pathogens in HIV patients. Pooled estimates of each helminthic infection were calculated. The odds ratio was also determined as a measure of the association between STH infection and the HIV status of the patients. Sixty-one studies were finally included in the meta-analysis, consisting of 16,203 human subjects from all over the world. The prevalence of Ascaris lumbricoides infection in HIV patients was found to be 8% (95% CI 0.06, 0.09), the prevalence of Trichuris trichiura infection in HIV patients was found to be 5% (95% CI 0.04, 0.06), the prevalence of hookworm infection in HIV patients was found to be 5% (95% CI 0.04, 0.06), and prevalence of Strongyloides stercoralis infection in HIV patients was found to be 5% (95% CI 0.04, 0.05). Countries from Sub-Saharan Africa, Latin America & Caribbean and Asia were identified with the highest burden of STH-HIV coinfection. Our analysis indicated that people living with HIV have a higher chance of developing Strongyloides stercoralis infections and decreased odds of developing hookworm infections. Our findings suggest a moderate level of prevalence of STH infections among people living with HIV. The endemicity of STH infections and HIV status both are partially responsible for the burden of STH-HIV coinfections

Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes

Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders