Blood Cancer

Question 1

Describe the altered cell fate in myelodysplasia

Answer 1

Increased apoptosis Reduced number terminally differentiated cells produced Partial block in differentiation leDs to the accumulation of immature cells

Question 2

List some therapeutic targets for acute myeloid leukaemia

Answer 2

Mutations in proliferation and survival FLT3 Oncogenic RAS KIT alleles PTPN11 - FLT3 inhibitors Mutations in differentiation and self-renewal Core binding factor Retinoic acid receptor MLL rearrangement -ATRA Target self-renewal WNT, notch, BMI1, HOX

Question 3

Describe the epigenetic of acute myeloid leukaemia

Answer 3

In the cancer cell DNMT, HDAC and MBP methylate

Question 4

List some single gene molecular abnormalities in acute myeloid leukaemia

Answer 4

FLT3 c-KIT CEBPalpha RUNX1 RAS NPM1 MLL partial tandem duplication WT1 IDH1/2 TET2 DNMT3A BCOR

Question 5

List the important transcription factors in blood cell differentiation

Answer 5

RUNX1 GATA2 C/EBPalpha DNMT3A TET2

Question 6

Give an example of a fusion protein in cancer and its treatment

Answer 6

PML-RARA Produced by the t(15:17) translocation in leukaemia Prevents transcription and therefore prevents cell differentiation Treat with retinoic acid which binds to the Retinoic Acid Receptor and releases the conplex that prevents transcription

Question 7

Describe core binding factor translocations in acute leukaemia

Answer 7

AML1-ETO aka RUNX1/RUNX1T1 Blocks differentiation at myeloblast stage

Question 8

Briefly describe FLT3 in acute myeloid leukaemia

Answer 8

Receptor tyrosine kinase ➡️RAS ➡️Akt Mutation leads to permanent activation, and continuous proliferation Associated with lower survival

Question 9

Summarise myeloproliferative disease

Answer 9

Excess of myeloid cells Primary polycythaemia- too many RBCs Primary thrombocythaemia- too many platelets Idiopathic myelofibrosis- too much marrow fibrosis Chronic myeloid leukaemia (CML)- too many neutrophils

Question 10

Summarise chronic myeloid leukaemia

Answer 10

Accumulation of myeloid progenitors High white blood cell count Large spleen Can transform into acute leukaemia

Question 11

What is the significance of Imatinib

Answer 11

BCR-Abl is a fusion protein that forms a tyrosine kinase with a markedly increased activity Imatinib inhibits the binding of ATP to ABL tyrosine kinase Selective for cancer cells

Question 12

List some next gen BCR ABL inhibitors and why are they needed

Answer 12

Nilotinib Dasatinib Bosutinib Ponatinib Needed to overcome the cancer cell mutations to overcome Imatinib, eg. Ponatinib is the only one that will work against the T315I mutation

Question 13

Summarise classical myeloid proliferative neoplasm

Answer 13

Polycythaemia Vera- increased red cell precursors in bone marrow Essential thrombocythaemia- increased megakaryocytes in marrow Large spleen Thrombosis Haemorrhage Itching Gout Clonal mutations- JAK2, CALR, MPL Treatment- aspirin, venesection, cytoreductive agents

Question 14

Summarise myelofibrosis

Answer 14

Fibrotic marrow Cytopenias Very large spleen -asymptomatic -spleen pain -fevers, sweats, back pain -infections Often a poor prognosis Blood transfusions Treatment- thalidomide, medroxyprogesterone, Ruxolitinib-JAK inhibitor

Question 15

Summarise myeloproliferative disease

Answer 15

Excess of myeloid cells Primary polycythaemia- too many RBCs Primary thrombocythaemia- too many platelets Idiopathic myelofibrosis- too much marrow fibrosis Chronic myeloid leukaemia (CML)- too many neutrophils

Question 16

List some lymphoid classifications

Answer 16

Precursor B/T neoplasms- acute lymphoblastic leukaemia (ALL) Mature B cell neoplasms- B cell lymphoma Mature T and NK cell neoplasm- T cell lymphoma Hodgkin lymphoma Immune deficiency associated lymphoproliferative disease

Question 17

Summarise chronic lymphocytic leukaemia

Answer 17

Proliferation of mature B cells Can infiltrate lymph nodes and spleen Indolent lymphoproliferative disease Mostly elderly

Question 18

Summarise multiple myeloma

Answer 18

Monoclonal proliferation of plasma cells Lytic bone lesions- fractures Paraprotein- renal failure Marrow suppression- anaemia

Question 19

What is the significance of EBV in lymphoma?

Answer 19

EBV infection leads to a latent pool of infected B lymphocytes which if coupled with immune suppression➡️ continued growth in a sense of immune control➡️ post transplant lymphoproliferative disease With chronic malaria➡️ chromosomal translocation and CMYC activation➡️ Burkitt lymphoma With co-factors➡️ cellular genetic changes➡️ Hodgkin lymphoma EBV encoded nuclear antigens (EBNA) can repress gene expression

Question 20

Name some underlying similar pathogenesis abnormalities found in lymphoproliferative diseases

Answer 20

Cytogenetic abnormalities- hyper diploid, the Philadelphia chromosome (BCR-ABL) Translocations forming fusion proteins- t(8;14) CMYC-IGH in burkitts Abnormalities in bone marrow microenvironment Some bacteria and viruses with other factors like immune suppression can cause some important lymphomas