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-
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
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)
Symptoms of chronic myeloid leukemia:
Weight loss
Night sweats
Itching left hypochondrial pain
Gout
Splenomegaly
BCR-ABL fusion protein with increased tyrosine kinase activity, think:
Chronic Myeloid Leukemia (CML)
First line of treatment for CML is:
Imatinib- a tyrosine kinase inhibitor
T(9;22) with eosinophilia, characteristic of ____
Chronic Myeloid Leukemia (CML)
Major cause of mortality in polycythemia vera is______
Thrombosis due to thickened blood
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
JAK 2 is a ________ kinase, which functions to regulate _____
Tyrosine
Cell division of myeloid stem cells
What is Gaisbock syndrome?
Type A fat drinking-smoking business man syndrome
Relative polycythemia with decreased plasma volume due to hypertension
Abnormal platelets and megakaryocyte hyperplasia n the bone marrow is ____, caused by mutation of _____
Essential thrombocythemia
JAK2 mutation
A defect of stem cell causing increased bone marrow stromal cell is _____
Myelofibrosis
Blood smear shows teardrop RBCs and immature myeloid cells, think:
Myelofibrosis
Which two myeloproliferative disorders can evolve into myelofibrosis?
PV and ET
Acute leukemias are proliferation of _______, while Chronic leukemias are proliferation of ______
Blasts
Mature cells
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
Acute myelogenous leukemia (AML) have _________ which differentiates from acute lymphoblastic leukemia
Aurer rods and MPO (myeloperoxidase)
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+
IL-3 is key in stimulating ________ stem cell to differentiate into the subtypes
Myeloid
Overproduction of myeloid progenitor is _______ leukemia
Acute myeloid
Signs and symptoms of AML:
Fatigue, Pallor, headache
Anemia, thrombocytopenia
Non-healing skin wounds, Minor infections
Bleeding gums
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
Genetic risks factors for AML:
Down syndrome
Fanconi anemia
Ataxia telengectesia
Environmental exposure risks for AML:
Benzene – from smoking, occupation exposure
Ionizing radiation
Smoking
What is the most common cytogenetic alteration seen in AML?
Translocation of (15;17) PMLRARA -> results in acute ProMYElocytic leukemia (M3 AML(
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
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)
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
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
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
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
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)
Marker of lymphoblasts is ________, and maker of pre B cell is _______
TdT+
CD10+
T/F: Acute lymphocytic leukemia 80% of cases are T-cell progenitor in origin
False; it is B-cell progenitor origin (involving CD10+)
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.
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
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
What is the most common leukemia overall (esp in adult)?
Chronic lymphocytic leukemia (CLL)
Often asymptomatic and slowly progressing
What is CLL?
Neoplastic proliferation of naïve B cells that express CD 5 and CD 20
Increased SMUDGE CELLS on blood smear
What is hairy cell leukemia?
Mature B cell leukemia with hair-looking projections
Mutation of the BRAF oncogene is ____
Hairy cell leukemia
What is BRAF?
BRAF is a serine threonine kinase
Mutation of BRAF leads to hair cell leukemia
Clinic findings of Hairy cell leukemia:
Dry tap marrow (marrow fibrosis) with massive splenomegaly and pancytopenia
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
