The expression values of apoptosis-regulating proteins were far beyond healthy control lymphocytes, which implicates the influence of microenvironmental factors. First, we showed that the intraindividual ex vivo apoptosis-related profiles of normal lymphocytes and AML blasts within the bone marrow of AML patients were highly correlated. Herein, we further explored this aspect of dynamic apoptosis regulation in AML. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. Zweegman, Sonja Cloos, Jacqueline Jimenez, Connie R.Įxpression of apoptosis-regulating proteins (B-cell CLL/lymphoma 2 - BCL-2, Myeloid Cell Leukemia 1 - MCL-1, BCL-2 like 1 - BCL-X and BCL-2-associated X protein - BAX) in acute myeloid leukemia ( AML) blasts at diagnosis is associated with disease-free survival. Wojtuszkiewicz, Anna Schuurhuis, Gerrit J. © 2016 by The American Society of Hematology.Įxosomes Secreted by Apoptosis-Resistant Acute Myeloid Leukemia ( AML) Blasts Harbor Regulatory Network Proteins Potentially Involved in Antagonism of Apoptosis*
Our work thus explains the pathophysiology of peripheral blood cytopenia in a relevant number of AML cases. Moreover, t(8 21) AML cases demonstrated the highest average MPL expression and lowest average platelet and absolute neutrophil counts among subgroups. Microarray analysis in an independent multicenter study cohort of 437 AML cases validated MPL expression as a central predictor of thrombocytopenia and neutropenia in AML. Mechanistic studies demonstrated that MPL hi blasts could indeed clear TPO, likely therefore leading to insufficient cytokine levels for nonleukemic hematopoiesis. Measuring serum concentration of thrombopoietin (TPO), a key regulator of hematopoietic stem cells and megakaryocytes, revealed loss of physiologic negative correlation with platelet count in AML cases with blasts expressing MPL, the thrombopoietin (scavenging) receptor. However, examining an initial cohort of 223 AML patients, we found no correlation between bone marrow blast content and cytopenia, questioning the displacement theory. A prevailing assumption states that AML spatially displaces nonleukemic hematopoiesis from the bone marrow. Rauch, Philipp J Ellegast, Jana M Widmer, Corinne C Fritsch, Kristin Goede, Jeroen S Valk, Peter J M Löwenberg, Bob Takizawa, Hitoshi Manz, Markus GĪlthough the molecular pathways that cause acute myeloid leukemia ( AML) are increasingly well understood, the pathogenesis of peripheral blood cytopenia, a major cause of AML mortality, remains obscure. MPL expression on AML blasts predicts peripheral blood neutropenia and thrombocytopenia.