Modelling timing in blood cancers

Dysregulation of biological processes in normal cells can lead to the abnormal growth of tumours. Oncogenesis requires the acquisition of advantageous mutations to expand in a fluctuating environment. Cancer cells gain these genetic and epigenetic alterations at different timing in their development, resulting in the formation of heterogeneous cell populations which interact and compete with each others inside tumours. At later stages, by escaping the immune system and acquiring malignant properties, some cancer cells manage to evade the primary tumour and spread in different organs to form metastases. Hence, tumour development in healthy tissues endure several biological changes whilst progressing and the order between these molecular and cellular events may modify prognosis. This thesis addresses the influence of biological event timing on blood cancer progression and clinical outcomes. It first investigates the therapeutic efficacy of p53 restoration in a lymphoma mouse model. While several therapy schedules are tested, all fail due to resistance emergence. Computational modelling establishes the cell dynamics in these tumours and how to use it to propose alternative treatment strategies. Data availability leads this work to explore the impact of molecular evolution in myeloid malignancies. Notably, one study has found that Myeloproliferative Neoplasms patients with both JAK2 and TET2 mutations have different disease characteristics with distinct mutation order. My analyses identify HOXA9 as a potential prognosis marker and biological switch responsible for patient stratification in these patients and in Acute Myeloid Leukemia. Additionally, a molecular network identifies the hematopoietic regulators involved in the branching evolution of Myeloproliferative Neoplasms. Further investigations of the Acute Myeloid Leukemia data show the possible involvement of APP, a gene associated to Alzheimer disease, in early cell fate commitment in hematopoiesis and in poor survival prognosis in undifferentiated leukemia when lowly expressed. Finally, this thesis examines the regulatory dynamics behind three clusters of Acute Myeloid Leukemia patients with distinct levels of HOXA9 and APP expression. By building a program inferring molecular motifs from biological observations, genes which may interact with HOXA9 and APP are identified.Microsoft Research and the MRC Cancer Unit

HOXA9 has the hallmarks of a biological switch with implications in blood cancers

Blood malignancies arise from the dysregulation of haematopoiesis. The type of blood cell and the specific order of oncogenic events initiating abnormal growth ultimately determine the cancer subtype and subsequent clinical outcome. HOXA9 plays an important role in acute myeloid leukaemia (AML) prognosis by promoting blood cell expansion and altering differentiation; however, the function of HOXA9 in other blood malignancies is still unclear. Here, we highlight the biological switch and prognosis marker properties of HOXA9 in AML and chronic myeloproliferative neoplasms (MPN). First, we establish the ability of HOXA9 to stratify AML patients with distinct cellular and clinical outcomes. Then, through the use of a computational network model of MPN, we show that the self-activation of HOXA9 and its relationship to JAK2 and TET2 can explain the branching progression of JAK2/TET2 mutant MPN patients towards divergent clinical characteristics. Finally, we predict a connection between the RUNX1 and MYB genes and a suppressive role for the NOTCH pathway in MPN diseases

HOXA9 has the hallmarks of a biological switch with implications in blood cancers

Blood malignancies arise from the dysregulation of haematopoiesis. The type of blood cell and the specific order of oncogenic events initiating abnormal growth ultimately determine the cancer subtype and subsequent clinical outcome. HOXA9 plays an important role in acute myeloid leukaemia (AML) prognosis by promoting blood cell expansion and altering differentiation; however, the function of HOXA9 in other blood malignancies is still unclear. Here, we highlight the biological switch and prognosis marker properties of HOXA9 in AML and chronic myeloproliferative neoplasms (MPN). First, we establish the ability of HOXA9 to stratify AML patients with distinct cellular and clinical outcomes. Then, through the use of a computational network model of MPN, we show that the self-activation of HOXA9 and its relationship to JAK2 and TET2 can explain the branching progression of JAK2/TET2 mutant MPN patients towards divergent clinical characteristics. Finally, we predict a connection between the RUNX1 and MYB genes and a suppressive role for the NOTCH pathway in MPN diseases