Leukemia Genetics

  1. Four main myeloproliferative disorders:
    • Polycythemia
    • Essential thrombocythemia
    • Myelofibrosis
    • Chronic myelogenous leukemia (CML)
  2. T/F: all four myeloproliferative disorders we learned are JAK2+, and Ph-
    False; CML is JAK2- Ph+ (no JAK2 mutation, but has Philadelphia chromosome), while the other three are JAK2+, Ph-
  3. What is Philadelphia chromosome?
    Translocation between q arms of chromosomes 9;22. Philadelphia chromosome refers to chromosome number 22, and this causes fusion BCR-ABL oncogene driver gene leading to CML and ALL
  4. What is the definition of myeloproliferative disorder?
    Excess production of one or more MATURE! myeloid hematopoietic lineages (essentially it is a type of chronic leukemia, but of the myeloid lineage)
  5. Symptoms of chronic myeloid leukemia:
    • Weight loss
    • Night sweats
    • Itching left hypochondrial pain
    • Gout
    • Splenomegaly
  6. BCR-ABL fusion protein with increased tyrosine kinase activity, think:
    Chronic Myeloid Leukemia (CML)
  7. First line of treatment for CML is:
    Imatinib- a tyrosine kinase inhibitor
  8. T(9;22) with eosinophilia, characteristic of ____
    Chronic Myeloid Leukemia (CML)
  9. Major cause of mortality in polycythemia vera is______
    Thrombosis due to thickened blood
  10. What is JAK2 V617F mutation?
    • A missense “gain of function” mutation causes hyperresponsiveness of erythroid progenitor cells to EPO
    • Seen in PV, essential thrombocythemia, and myelofibrosis
  11. JAK 2 is a ________ kinase, which functions to regulate _____
    • Tyrosine
    • Cell division of myeloid stem cells
  12. What is Gaisbock syndrome?
    • Type A fat drinking-smoking business man syndrome
    • Relative polycythemia with decreased plasma volume due to hypertension
  13. Abnormal platelets and megakaryocyte hyperplasia n the bone marrow is ____, caused by mutation of _____
    • Essential thrombocythemia
    • JAK2 mutation
  14. A defect of stem cell causing increased bone marrow stromal cell is _____
    Myelofibrosis
  15. Blood smear shows teardrop RBCs and immature myeloid cells, think:
    Myelofibrosis
  16. Which two myeloproliferative disorders can evolve into myelofibrosis?
    PV and ET
  17. Acute leukemias are proliferation of _______, while Chronic leukemias are proliferation of ______
    • Blasts
    • Mature cells
  18. T/F: acute leukemias presents with anemia (low rbc), thrombocytopenia (hemorrhagic bleeding) or neutropenia (infection)
    True; despite having elevated White count, these are blasts that are released
  19. Acute myelogenous leukemia (AML) have _________ which differentiates from acute lymphoblastic leukemia
    Aurer rods and MPO (myeloperoxidase)
  20. Which of the 4 leukemias are most often seen in children under 15 years of age?
    • Acute lymphblastic leukemia (ALL)
    • While all the rest are seen around age 60+
  21. IL-3 is key in stimulating ________ stem cell to differentiate into the subtypes
    Myeloid
  22. Overproduction of myeloid progenitor is _______ leukemia
    Acute myeloid
  23. Signs and symptoms of AML:
    • Fatigue, Pallor, headache
    • Anemia, thrombocytopenia
    • Non-healing skin wounds, Minor infections
    • Bleeding gums
  24. Primary AML vs secondary AML:
    • Primary AML is accumulation of somatic mutations in hematopoietic stem and progenitor cells
    • Secondary AML is basically a pre-existing hematologic condition such as MPD/ CML, chemotherapy that transformed into AML
  25. Genetic risks factors for AML:
    • Down syndrome
    • Fanconi anemia
    • Ataxia telengectesia
  26. Environmental exposure risks for AML:
    • Benzene – from smoking, occupation exposure
    • Ionizing radiation
    • Smoking
  27. What is the most common cytogenetic alteration seen in AML?
    Translocation of (15;17) PMLRARA -> results in acute ProMYElocytic leukemia (M3 AML(
  28. Class I mutations in AML vs Class II mutations in AML:
    • Class I – activates signal transduction pathway which leads to uncontrolled proliferation of leukemic cells
    • Class II mutations – results in fusion protein that leads to impaired differentiation of leukemic cells
  29. T/F: AML is multistep process that requires at least two genetic abnormalities for the development of disease
    True; needs class 1 and 2 mutations (activate signal transduction and fusion protein respectively)
  30. What is t(15;17) PML-RARA?
    It is a subset of AML mutation that results in acute promyelocytic leukemia (APL) which involves translocation of the retinoic acid receptor (RAR) on chromosome 17 to chromosome 15
  31. What is Acute Promyelocytic leukemia?
    • T(15;17) PML-RARA- aka fusion of PML and RARA resulting in a hybrid protein that leads to abnormal accumulation of immature promyelocytes
    • Increased risk for DIC due to increased primary granules from the abnormal promyelocytes
  32. What is the treatment for acute promyelocytic leukemia? What is the side effect?
    • PML treatment, all trans retinoic acid (vitamin A) and arsenic trioxide
    • Side effect is retinoic acid syndrome- which is attributed to capillary leaking from cytokine release as the promyelocytes differentiate
  33. How does treatment of M3 AML work (acute promyelocytic leukemia)?
    All-trans retinoic acid (ATRA) dissociated the NCOR-HDACL complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes after which these differentiated malignant cells undergo spontaneous apoptosis on their own
  34. Most common Childhood cancer:
    • Acute lymphocytic leukemia (aka acute lymphoblastic)
    • Common in children with Down syndrome (trisomy 21) after 5 years of age (vs acute megaloblastic leukemia (a subtype of AML) is often seen in children with down syndrome before 5 years old)
  35. Marker of lymphoblasts is ________, and maker of pre B cell is _______
    • TdT+
    • CD10+
  36. T/F: Acute lymphocytic leukemia 80% of cases are T-cell progenitor in origin
    False; it is B-cell progenitor origin (involving CD10+)
  37. There are two driver mutations in ALL. Driver 1 mutation occurs _______, while driver 2 mutation occurs ______
    • Prenatally during embryogenesis
    • After birth – ie. Through infection, stress, nutrition (environmental causes)
    • Need both to occur, otherwise just having one is not sufficient to cause disease.
  38. What is t(12;21)ETV6-RUNX1?
    • One of the most common driver 1 mutation for ALL. This is the one with the good prognosis, Ph-
    • ETV6 repression domain dominates and turns off the RUNX1 activation domain so differentiation cannot occur
  39. T/F: ALL is commonly seen in children, but could occur in adult. In adult, ALL has poor prognosis due to Philadelphia chromosome t(9;22)
    True
  40. What is the most common leukemia overall (esp in adult)?
    • Chronic lymphocytic leukemia (CLL)
    • Often asymptomatic and slowly progressing
  41. What is CLL?
    • Neoplastic proliferation of naïve B cells that express CD 5 and CD 20
    • Increased SMUDGE CELLS on blood smear
  42. What is hairy cell leukemia?
    Mature B cell leukemia with hair-looking projections
  43. Mutation of the BRAF oncogene is ____
    Hairy cell leukemia
  44. What is BRAF?
    • BRAF is a serine threonine kinase
    • Mutation of BRAF leads to hair cell leukemia
  45. Clinic findings of Hairy cell leukemia:
    Dry tap marrow (marrow fibrosis) with massive splenomegaly and pancytopenia
  46. What is Vemurafenib used to treat?
    it is a BRAF inhibitor, so it changes the morphology of hairy B cell to smooth B cells and eventually to apoptosis
Author
lykthrnn
ID
348555
Card Set
Leukemia Genetics
Description
HemeOnc Midterm 2
Updated